PRESENTED BY: ASHISH VYAS PGT,ORAL AND MAXILLOFACIAL SURGERY RDC,GUWAHATI

GUIDED BY:DR A.K.ADHYAPOK PRINCIPAL AND H.O.D DEPARTMENT OF ORAL AND MAXILLOFACIAL SURGERY RDC,GUWAHATI

INTRODUCTION
Many,

if not most, ailments of the body cause pain. Pain includes not only the perception of an uncomfortable stimulus but also the response to that perception. Pain, is currently considered as the fifth vital sign that should be included in the routine patient assessment (Arnstein, 2005). We must recognize that pain is also an important component of the persons protective system. Without the sense of pain, we would not be immediately aware of injuries to tissues.

DEFINITION
In 1900, Sherrington, was among the first modern

neural scientists to define pain as the psychical adjunct to an imperative protective reflex. This is a concise definition, and it underlines the urgent primitive dimension of pain-the motor response that is teleologically oriented to remove tissue from potentially damaging insults. The International Association for the Study of Pain(2004) has proposed the following definition: pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

 Thus, even though traditionally viewed as an entirely

sensory phenomenon, pain differs fundamentally from other conventional sensory modalities in that numerous and diverse types of stimuli are capable of initiating a complex multifaceted pain response.
In many ways, pain transcends attempts to define it

and is best regarded as an experience involving both a physiologic sensation and an emotional or, as is the case for nonverbal animals, behavioral reaction to that sensation.
Pain includes not only the perception of an

uncomfortable stimulus but also the response to that perception.

Pain Is a Protective Mechanism

Pain is a protective mechanism which alerts us to a

problem and prompts us to take action. Even such simple activities as sitting for a long time on the ischemia can cause tissue destruction because of lack of blood flow to the skin where it is compressed by the weight of the body. When the skin becomes painful as a result of the ischemia, the person normally shifts weight subconsciously. But a person who has lost the pain sense, as after spinal cord injury, fails to feel the pain and, therefore, fails to shift. This soon results in total breakdown and desquamation of the skin at the areas of pressure.

1. SPECIFICITY THEORY 2. PATTERN THEORY 3. GATE CONTROL THEORY 4. BEYOND THE GATE

(CONCEPT OF NEUROMATRIX)

SPECIFICITY THEORY
The Specificity theory was originated in Greece .This

theory was highlighted by Descartes in 1664 and described by VON FREY in 1894. Descartes explained that when someone pulls the rope to ring the bell, the bell rings in the tower. Hence, specificity theory suggests that pain is caused by injury or damage to body tissue. The damaged nerve fibres in our bodies sends direct messages through the specific pain receptors and fibres to the pain center, the brain which causes the individual to feel pain. This theory suggest that there is a strong link between pain and injury and that the severity of injury determines the amount of pain experienced by the person.

Thus this theory does not allow for any possible changes of psychological origin, such as might result from attention or from past experiences that give a particular meaning to a particular situation.

PATTERN THEORY
It was put forward by GOLDSCHEIDER. The Pattern theory was incorporated into the specificity

theory which added more concepts to explain and extended its hypothesis of pain The pattern theory states that nerve fibres that carry pain signals can also transmit messages of cold, warmth and pressure can also transfer pain if an injury or damage to body tissue occurs. These theories added to the linear ascending pathway various relays that begin the process of integrating the activity of nerve fibres that have different receptive properties. The Specificity theory and Pattern theory are not

GATE CONTROL THEORY

In 1965, Melzack and Wall proposed the gate control

theory of pain. It is the first theory of pain that incorporated the central control processes of the brain. The gate control theory of pain proposed that the transmission of nerve impulses from afferent fibers to spinal cord transmission (T) cells is modulated by a gating mechanism in the spinal dorsal horn. This gating mechanism is influenced by the relative amount of activity in large small diameter fibers, so that large fibers tend to inhibit transmission (close the gate) whereas small fibers tend to facilitate transmission (open the gate).

 In addition, the spinal gating mechanism is influenced by

nerve impulses that descend from the brain. When the output of the spinal T cells exceeds a critical level, it activates the action system:-those neural areas that underlie the complex, sequential patterns of behavior and experience characteristics of pain. The theory's emphasis on the modulation of inputs in the spinal dorsal horns and the dynamic role of the brain in pain processes had a clinical as well as a scientific impact. Psychological factors, which were previously dismissed as "reactions to pain" were now seen to be an integral part of pain processing, and new avenues for pain control by psychological therapies were opened. Similarly. cutting nerves and pathways was gradually replaced by a host of methods to modulate the input. Physical therapists and other health-care professionals who use a multitude of modulation techniques were brought into the picture. and transcutaneous electrical nerve stimulation (TENS) became an important modality for the treatment of

The large (L) and small (S) fibers project to the substantia gelatinosa (SG) and first central transmission (T) cells. The central control trigger is represented by a line running from the large fiber system to central control mechanisms, which in turn project back to the gate control system. The T cells project to the entry cells of the action system. +. excitation: -, inhibition.

 This concept can be explained by that the soldiers

during World War II reported slight pain even though they had sever damage to tissue due to the battle. These soldiers had positive thinking and were distracted because injury meant that the soldiers would be allowed to go home or sustain no further injury. The gate control theory states that non painful stimulus such as distraction competes with the painful impulse to reach the brain. This rivalary limits the number of impulses that can be transmitted in the brain by creating the hypothetical gate. The specificity theory and the pattern theory suggests that pain occurs only due to damage to body tissue while the gate control theory claims that pain may be experienced without any physical injury and individuals

BEYOND THE GATE (CONCEPT OF NEUROMATRIX)

It is evident that the gate control theory has taken us a

long way. Yet as historians of science have pointed out, good theories are instrumental in producing facts that eventually require a new theory to incorporate them. And this is what has happened. Melzack's analysis of phantom limb phenomena, particularly the astonishing reports of a phantom body and severe phantom limb pain in people with a total thoracic spinal cord section, has led to four conclusions that point to a new conceptual model of the nervous system.

 First, because the phantom limb (or other body part)

feels so real, it is reasonable to conclude that the body we normally feel is subserved by the same neural processes in the brain as the phantom; these brain processes are normally activated and modulated by inputs from the body but they can act in the absence of any inputs. Second, all the qualities we normally feel from the body, including pain, are also felt in the absence of inputs from the body; from this we may conclude that the origins of the patterns that underlie the qualities of experience lie in neural networks in the brain; stimuli may trigger the patterns but do not produce them. Third, the body is perceived as a unity and is identified as the "self," distinct from other people and the surrounding world. The experience of a unity of such diverse feelings,

 Fourth, the brain processes that underlie the body-self are

"built in" by genetic specification, although this built-in substrate must, of course, be modified by experience. These conclusions provide the basis of the new conceptual model.

OUTLINE OF THE THEORY

The anatomic substrate of the body-self, Melzack proposed,

is a large, widespread network of neurons that consists of loops between the thalamus and cortex as well as between the cortex and limbic system. He has labeled the entire network, whose spatial distribution and synaptic links are initially determined genetically and are later sculpted by sensory inputs, as a NEUROMATRIX. The loops diverge to permit parallel processing in different components of the neuromatrix and converge repeatedly to permit interactions between the output products of processing. The repeated cyclical processing and synthesis of nerve

 The neurosignature of the neuromatrix is imparted on all

nerve impulse patterns that flow through it; the neurosignature is produced by the patterns of synaptic connections in the entire neuromatrix. All inputs from the body undergo cyclical processing and synthesis so that characteristic patterns are impressed on them in the neuromatrix. Portions of the neuromatrix are specialized to process information related to major sensory events (such as injury, temperature change, and stimulation of erogenous tissue) and may be labeled as neuromodules that impress subsignatures on the larger neurosignature. The neurosignature, which is a continuous output from the body-self neuromatrix, is projected to areas in the brain ,the sentient neural hub-in which the stream of nerve impulses (the neurosignature modulated by ongoing inputs) is converted into a continually changing

 The neurosignature patterns may also activate a

neuromatrix to produce movement.

That is, the signature patterns bifurcate so that a

pattern proceeds to the sentient neural hub (where the pattern is transformed into the experience of movement) and a similar pattern proceeds through a neuromatrix that eventually activates spinal cord neurons to produce muscle patterns for complex actions.

BODY SELF NEUROMATRIX

The body is felt as a unity with different qualities at different

times. Melzack proposed that the brain mechanism that underlies the experience also comprises a unified system that acts as a whole and produces a neurosignature pattern of a whole body. The conceptualization of this unified brain mechanism lies at the heart of the new theory, and the word "neuromatrix" best characterizes it. The neuromatrix (not the stimulus, peripheral nerves or "brain center") is the origin of the neurosignature; the neurosignature originates and takes form in the neuromatrix. Although the neurosignature may be triggered or modulated by input, the input is only a "trigger and does not produce the neurosignature itself.

 The array of neurons in a neuromatrix is genetically

programmed to perform the specific function of producing the signature pattern.

The final, integrated neurosignature pattern for the body-

self ultimately produces awareness and action.

The neuromatrix, distributed throughout many areas of

the brain, comprises a widespread network of neurons that generates patterns, processes information that flows through it, and ultimately produces the pattern that is felt as a whole body.
The stream of neurosignature output with constantly

varying patterns riding on the main signature pattern

CONCEPTUAL REASONS FOR NEUROMATRIX

It is difficult to comprehend how individual bits of

information from skin, joints, or muscles can all come together to produce the experience of a coherent, articulated body. At any instant in time, millions of nerve impulses arrive at the brain from all the body's sensory systems, including the proprioceptive and vestibular systems. How can all this be integrated in a constantly changing unity of experience? Where does it all come together? Melzack conceptualized a genetically built in neuromatrix for the whole body, producing a characteristic neurosignature for the body that carries with it patterns for the myriad qualities we feel.

 The neuromatrix, as Melzack conceived of it, produces

a continuous message that represents the whole body in which details are differentiated within the whole as inputs come into it. We start from the top, with the experience of a unity of the body, and look for differentiation of detail within the whole. The neuromatrix, then, is a template of the whole, which provides the characteristic neural pattern for the whole body (the body's neurosignature) as well as subsets of signature patterns (from neuromodules) that relate to events at (or in) different parts of the body. There are no external equivalents to stinging, smarting, tickling, itch; the qualities are produced by built in neuromodules whose neurosignatures innately produce the qualities.

 The inadequacy of the traditional peripheralist view

becomes especially evident when we consider paraplegics with high-level complete spinal breaks. In spite of the absence of inputs from the body, virtually every quality of sensation and affect is experienced. The neuromatrix is a psychologically meaningful unit, developed by both heredity and learning, that represents an entire unified entity. The phenomenon of phantom limbs has allowed us to examine some fundamental assumptions in psychology. One assumption is that sensations are produced only by stimuli and that perceptions in the absence of stimuli are psychologically abnormal. Yet phantom limbs, as well as phantom seeing, indicate this notion is wrong.

 The brain does more than detect and analyze inputs; it generates perceptual experience even when no external inputs occur. In short, phantom limbs are a mystery only if we assume the body sends sensory messages to a passively receiving brain. Phantoms become comprehensible once we recognize that the brain generates the experience of the body. Sensory inputs merely modulate that experience; they do not directly cause it.

TYPES OF PAIN
PAIN

PHYSIOLOGICAL PATHOLOGICAL

INFLAMMATORY NEUROPATHIC

PHYSIOLOGIC PAIN
An important conceptual breakthrough in understanding pain

physiology is the recognition that the pain that occurs after most types of noxious stimulation is usually protective and quite distinct from the pain resulting from overt damage to tissues or nerves. This first type of pain is termed physiologic pain. It plays an integral adaptive role as part of the body's normal defense mechanisms, warning of contact with potentially damaging environmental insults and initiating behavioral and reflex avoidance strategies. It is also often referred to as nociceptive pain because it is only elicited when intense noxious stimuli threaten to injure tissue. Although the extrapolation of this physiologic model of pain to the clinical setting has several inherent limitations, an

PATHOLOGIC PAIN
The traditional stimulus-response model of physiologic

pain is conceptually appealing and has laid the foundation for a more comprehensive understanding of nociceptive pathways. Nevertheless, it must be recognized that physiologic pain alone is a rare entity in the clinical setting. In most situations, the noxious stimulus is not transient and may be associated with significant tissue inflammation and nerve injury. Under such circumstances, the classic "hard-wired system becomes less relevant, and dynamic changes in the processing of noxious input are evident in both peripheral and central nervous systems. This type of pain is called pathologic pain (because it implies that the tissue damage has already occurred)

NOCICEPTIVE PROCESSING
The physiologic component of

pain is termed nociception, which consists of the processes of transduction, transmission, and modulation of neural signals generated in response to an external noxious stimulus. It is a physiologic process that results in the conscious perception of pain when carried to completion. In its simplest form, the pathway can be considered as

PHERIPHERAL NOCICEPTORS
The first process of nociception involves the encoding of

mechanical, chemical, or thermal energy into electric impulses by specialized nerve endings termed nociceptors. Unlike other specialized somatic sensory receptors, nociceptors exist as free nerve endings of primary afferent neurons and function to preserve tissue homeostasis by signaling actual or potential tissue injury. As such, they have considerably higher stimulus thresholds for activation than thermoreceptors or lowthreshold mechanoreceptors, which are capable of generating spontaneous action potentials under ambient conditions.

 Nociceptors are unique among sensory receptor classes

in that under certain circumstances, repeated activation actually lowers their threshold and results in an enhanced response to subsequent stimuli. This phenomenon, is called sensitization. Interestingly, nociceptors are also capable of exhibiting fatigue or habituation, a characteristic of all other sensory systems whereby repeated or sustained presentation of a noxious stimulus actually leads to a diminished response. Thus, the composite afferent message induced by a given stimulus is complex, resulting from the activation of various types of nociceptors with differing thresholds and response characteristics.

(A)ASCENDING

PATHWAYS

(B)DESCENDING

PATHWAYS

AFFERENT NERVE FIBRES

Conventional nomenclature based on

neurophysiologic studies has classified nociceptors into two categories: A-fiber (A delta) mechanoheat nociceptors and Cfiber mechanoheat nociceptors according to their associated afferent nerve fibers and stimulus sensitivities. A delta fibers are large diameter thinly myelinated axons and consequently conduct impulses rapidly. In contrast, transmission in the smaller unmyelinated C fibers is much slower and acts to reinforce the immediate response of the A fibers, becoming increasingly important as the duration of the stimulus

 These bers are small, thinly myelinated neurons, 1 to

A-DELTA FIBRES

5 m in diameter, with conduction velocities in the range of 5 to 30 m/s. A-delta bers have small receptive elds and are relatively modality specic. This latter quality is a function of specic, highthreshold ion channels on the free endings of A-delta afferents that are differentially activated by distinct high intensity thermal or mechanical input (Julius & Basbaum, 2001). A-delta thermoresponsive bers respond to extremes of temperature. One population is activated by noxious heat, with an initial response threshold in the range of 40 to 45 C. Response function increases directly, although not necessarily linearly, as a consequence of temperature

 A second population, high threshold cold afferents,

responds to cold temperatures at or below a threshold of approximately 8C, with increasing cold sensitivity to temperatures less than 25C (Price & Dubner, 1977). A-delta mechanoreceptive afferents are activated by high-intensity mechanical stimulation (deep pressure, stab, pinch, stretch), although these bers may be sensitized by, and become secondarily responsive to, noxious heat. Unlike A-delta thermal afferents, sensitized A-delta mechanoreceptive afferents respond to suprathreshold heat (usually in excess of 50 to 55C) and/or repetitive presentation of noxious heat, rather to a singular exposure to a heat stimulus at or above the nociceptive threshold (Kumazawa & Perl, 1976).

C FIBRES
C-bers are small, unmyelinated afferents with broader

receptiv elds than A-delta bers. C-ber diameters range from 0.25 to 1.5 m, and the absence of myelin leads to slower conductance velocities that vary from 0.5 to 2 m/s. This slower conductance together with the broad receptor elds subserve clinical second pain, a diffuse, poorly localized burning, throbbing, or gnawing sensation that follows and that is temporally and qualitatively distinct from the initial sensation of rst pain (Torebjork, 1974). Numerically, C-bers constitute the majority of primary nociceptive afferent innervation of cutaneous tissue.

 C-bers are polymodal, and can be activated by

thermal, mechanical, and chemical stimuli. In addition to responding to noxious (thermal, mechanical, and chemical) stimuli, C-ber polymodal afferents may be sensitized by substrates of the inammatory cascade (e.g., prostaglandin-E2, bradykinin) that are released following thermal or mechanical insult (Gold et al., 1998; Levine & Reichling, 1999). Once sensitized, these C-bers can be activated by certain types of nonnoxious, low-intensity stimulation. This may account for the persistent second pain and hyperalgesia that occurs following burn injury or other inammatory states (Rowbotham & Fields, 1996). In this light, C-bers may contribute to multiple sensations from a painful region.

 C-bers also innervate muscle tissue, localized to the

intrabril matrix, tendons, and areas surrounding the vascular walls (Iggo, 1974). C-ber muscle afferents are polymodal and are responsible for the nociceptive response to intense mechanical stimulation (Jones, Newham, Obletter, & Giamberardino, 1987) that produces numerous substances as a consequence of both aerobic and anaerobic metabolism. C-bers innervating muscular tissues are activated by H ions as a constituent of the acidic postmetabolic environment (Mills, Newham, & Edwards, 1982) as well as end products of inammation due to exerciseinduced micro- or macrotraumatic insult (including bradykinin, histamine, and 5-HT; Vecchiet, Giamberardino, & Marini, 1987), mechanical distention

Primaty afferent pain transmission. First pain and second pain sensations after a noxious stimulus (A). The first pain sensation is abolished when the A fibers are blocked (B), while the second pain sensation is abolished when the C fibers are blocked (C)

NEUROCHEMISTRY OF PRIMARY AFFERENT PAIN

The principal neurochemical mediator at the synaptic

cleft between primary afferent nociceptors and dorsal horn cells is glutamate. Postsynaptically, glutamate is capable of binding to two types of discrete receptors (Woolf, 2004). The rst, the AMPA (alpha-amino-3-hydroxy-5methylisoxazole-4 propionic acid) receptor, appears to be the initial or rst molecular target for glutamate binding. Glutamate-induced AMPA receptor activation evokes a ligand-gated sodium current in postsynaptic secondorder neurons of the dorsal horn that produces a rapid depolarization.

 AMPA receptor-mediated depolarization modulates

glutamate-induced activation of the second class of receptor, the N-methyl-D-aspartate (NMDA) receptor, by allosteric modulation of magnesium binding to a shared or cooperative domain of the NMDA receptors.
With persistent AMPA receptor activation, the rise in

intracellular sodium displaces a magnesium gate from the NMDA receptor, thereby increasing its sensitivity or releasing it from an inaccessible conguration to actively bind glutamate (Woolf & Salter,2000).

AMPA RECEPTOR
Each AMPA receptor contains 4 subunits with integral

glutamate binding sites that surround a central cation channel designated as GluR1 , GluR2 , GluR3 , and GluR4. Agonist binding at two or more sites activates the receptor, opening the channel and allowing passage of Na ions into the cell. This brief increase in Na ions ux depolarizes secondorder spinal neurons, allowing noxious signals to be rapidly transmitted to supraspinal sites of perception. The AMPAR's permeability to calcium and other cations, such as sodium and potassium, is governed by the GluR2 subunit. If an AMPAR lacks a GluR2 subunit, then it will be permeable to sodium, potassium, and calcium.

NMDA RECEPTORS
NMDARs display a number of unique properties that

distinguish them from other ligand-gated ion channels. First, the receptor controls a cation channel that is highly permeable to monovalent ions and calcium. Second, simultaneous binding of glutamate and glycine, the coagonist, is required for efficient activation of NMDAR. Third, at resting membrane potential the NMDAR channels are blocked by extracellular magnesium and open only on simultaneous depolarization and agonist binding.

 Native NMDARs are composed of NR1, NR2 (A, B, C,

and D) and NR3 (A and B) subunits. Co-expression studies have demonstrated that formation of functional NMDAR channels requires a combination of NR1, an essential channel-forming subunit, and at least one of the NR2 subunits. Most obvious subunit-dependent properties of NMDARs are their single-channel conductance and sensitivity to magnesium block. For example, the NR2A or NR2B subunits-containing NMDARs generate high conductance channel openings with a high sensitivity for blocking by magnesium, whereas NR2C- or NR2D-containing receptors give rise to low conductance openings with a lower sensitivity to magnesium.

 Peripheral nociceptive fibers express NR2B and NR2D

subunits, whereas NR2A subunits appear to be absent from the peripheral terminals of primary afferents.
Because NR2B-selective antagonists (e.g.

IFENPRODIL) potentiate NMDAR inhibition by endogenous protons , this mode of action may be beneficial under conditions of tissue injury, ischemia, or inflammation (presumably accompanied by acidosis) when a greater degree of inhibition of NMDARs can be expected in the affected tissues than normal .
This could also explain the improved efficacy of NR2B-

selective antagonists under these conditions.

 While brief, suprathreshold primary nociceptor activity

causes the release of glutamate, prolonged and/or intense C-ber activation induces the release of the substance-P (Cao et al., 1998).
Initially, substance-P binds postsynaptically to

neurokinin-2 (NK-2) receptors on second-order dorsal horn neurons.

However, with more prolonged excitation, substance-P

also binds to NK-1 receptors to activate G protein mediated, metabotropic, slow onset, durable shifts in membrane potential (Woolf, 2004).

Dorsal Horn Neurons

Cell bodies of both types of afferent nociceptive nerve

fibers are contained in the dorsal root ganglia and extend axons to synapse with dorsal horn neurons within the gray matter of the spinal cord.
It is in the dorsal horn that initial integration and

modulation of nociceptive input occur.

Before going into details of dorsal horn neurons, first we

will understand its organisation.

ORGANISATION OF DORSAL HORN

The posterior horn (posterior cornu, dorsal

horn, spinal dorsal horn) of the spinal cord is the dorsal (more towards the back) grey matter of the spinal cord. The dorsal horn is a major receptive zone (zone of termination) of primary afferent fibres, which enter the spinal cord through the dorsal roots of spinal nerves. Organisation of the dorsal horn is in the form of different laminae called as REXEDS LAMINAE.

REXEDS LAMINAE

 The Rexed laminae comprise a system of ten layers

of grey matter (I-X), identified in the early 1950s by Bror Rexed to label portions of the spinal cord.
The laminae are numbered sequentially in a dorsoventral

sequence .
Laminae I-IV correspond to the head of the dorsal horn,

and are the main receiving areas for cutaneous primary afferent terminals and collateral branches.
Many complex polysynaptic reflex paths (ipsilateral,

contralateral, intrasegmental and intersegmental) start from this region and many long ascending tract fibres which pass to higher levels arise from it.

LAMINA I(LAMINA MARGINALIS)

It is a very thin layer with an ill-defined boundary at the

dorsolateral tip of the dorsal horn. It has a reticular appearance, reflecting its content of intermingling bundles of coarse and fine nerve fibres. It contains small, intermediate and large neuronal somata, many of which are fusiform in shape.

LAMINA II
It occupies most of the head of the dorsal horn and

consists of densely packed small neurones responsible for its dark appearance in Nissl-stained sections. With myelin stains, Lamina II is characteristically distinguished from adjacent laminae by the almost total lack of myelinated fibres. Lamina II corresponds to the substantia gelatinosa.

LAMINA III
It consists of somata which are mostly larger, more

variable and less closely packed than those in lamina II. It also contains many myelinated fibres. Some workers consider that the substantia gelatinosa contains part or all of lamina III as well as lamina II. The ill-defined nucleus proprius of the dorsal horn corresponds to some of the cell constituents of laminae III and IV.

LAMINA IV
It is a thick, loosely packed, heterogeneous zone

permeated by fibres. Its neuronal somata vary considerably in size and shape, from small and round, through intermediate and triangular, to very large and stellate.

LAMINA V
Lamina V is a thick layer which includes the neck of the

dorsal horn. It is divisible into a lateral third and medial two-thirds. Both have a mixed cell population but the former contains many prominent well-staining somata interlaced by numerous bundles of transverse, dorsoventral and longitudinal fibres.

LAMINA VI
Lamina VI is most prominent in the limb enlargements.

It has a densely staining medial third of small, densely

packed neurones and a lateral two-thirds containing larger, more loosely packed, triangular or stellate somata. Lamina VI corresponds approximately to the base of the dorsal horn. V and VI receive most of the terminals of Laminae
proprioceptive primary afferents and profuse corticospinal projections from the motor and sensory cortex and subcortical levels, which suggests their intimate involvement in the regulation of movement.

LAMINA VII
Lamina VII includes much of the intermediate (lateral)

horn. It contains prominent neurones of Clarke's column (nucleus dorsalis, nucleus thoracis, thoracic nucleus) and intermediomedial and intermediolateral cell groupings. The lateral part of lamina VII has extensive ascending and descending connections with the midbrain and cerebellum (via the spinocerebellar, spinotectal, spinoreticular, tectospinal, reticulospinal and rubrospinal tracts) and is thus involved in the regulation of posture and movement. Its medial part has numerous propriospinal reflex

LAMINA VIII
Lamina VIII spans the base of the thoracic ventral horn

but is restricted to its medial aspect in limb enlargements. Its neurones display a heterogeneous mixture of sizes and shapes from small to moderately large. Lamina VIII is a mass of propriospinal interneurones. It receives terminals from the adjacent laminae, many commissural terminals from the contralateral lamina VIII, and descending connections from the interstitiospinal, reticulospinal and vestibulospinal tracts and the medial longitudinal fasciculus. The axons from these interneurones influence motor neurones bilaterally, perhaps directly but more probably by excitation of small neurones supplying

LAMINA IX
Lamina IX is a complex array of cells consisting of and

motor neurones and many interneurones. The large motor neurones supply motor end-plates of extrafusal muscle fibres in striated muscle.
The smaller motor neurones give rise to small-diameter

efferent axons (fusimotor fibres), which innervate the intrafusal muscle fibres in muscle spindles. There are several functionally distinct types of motor neurone. The 'static' and 'dynamic' responses of muscle spindles have separate controls mediated by static and dynamic fusimotor fibres, which are distributed variously to nuclear chain and nuclear bag fibres.

LAMINA X
Lamina X surrounds the central canal and

consists of the dorsal and ventral grey commissures.

 The majority of A delta fibers terminate in the most

superficial layer, lamina I (also called the marginal zone), with some fibers projecting more deeply to lamina V.

Most C fibers are also destined for the superficial dorsal

horn, with the focus in lamina II (the substantia gelatinosa).

TYPES OF DORSAL HORN NEURONS

Primary afferent axons may form direct or indirect

connections with one of three functional populations of dorsal horn neurons: (1) Inteneurons: frequently divided into excitatory and inhibitory subtypes, which serve as relays and participate in local processing; (2) Propriospinal Neurons, which extend over multiple spinal segments and are involved in segmental reflex activity and interactions among stimuli acting at separate loci; and (3) Projection Neurons, which participate in rostral transmission by extending axons beyond the spinal cord to terminate in supraspinal centers such as the midbrain and the cortex. All three components are interactive and are essential for the processing of nociceptive information, which

TYPES OF PROJECTION NEURONS

Projection neurons have been subclassified into three

groups:1. NOCICEPTIVE SPECIFIC (NS) NEURONS: concentrated in lamina I and lamina II, are excited solely by noxious mechanical or thermal input from both A Delta and C fibers. They are arranged somatotopically and respond to afferent impulses originating from discrete topographic areas. 2. WIDE DYNAMIC RANGE (WDR) NEURONS: predominate in lamina V and receive innocuous input from low-threshold mechanoreceptors as well as nociceptive information. They respond in a graded manner over a larger receptive field than do NS neurons and often receive convergent deep and visceral input. Although WDR neurons are considered to be ambiguous with regard to modality, they generate their strongest

The spinothalamic tract is somatotopically organized. Axons from neurons in rostral segments of the spinal cord ascend medially relative to axons orginating from caudal segments. The somatotopy is maintained within the major target nucleus of the thalamus, the ventroposterior lateral nucleus. Primary sensory cortex is somatotopically organized with lumbar segments (e.g.leg) represented medially within the postcentral gyrus and cervical

WIDE DYNAMIC RANGE NEURONS

These neurons have three interesting functional

characteristics: (1) Given their connectivity, the neurons display excitation driven by low and high threshold afferent input. This gives the WDR neurons the property of responding with increased frequency as the stimulus intensity is elevated; they have a wide dynamic response range. Light innocuous touch evokes activity that increases as the intensity of pressure or pinch is increased. (2) Organ convergence: Depending on the spinal level, WDR neurons may be activated by both somatic stimuli and by activation of visceral afferent. This convergence results in a comingling of excitation for a visceral organ and a specific area of the body surface and leads to

 These viscerosomatic and

musculosomatic convergences onto dorsal horn neurons underlie the phenomenon of referred visceral or deep muscle or bone pain to particular body surfaces. (3) Low-frequency (above 0.33 Hz) repetitive stimulation of C fibers, but not A fibers, produces a gradual increase in the frequency discharge until the neuron is in a state of virtually continuous discharge ("wind-up").

Example of organ convergence: T1 and T5 root stimulation activates WDR neurons that are also excited by coronary artery occlusion.These results indicate that the phenomenon of referred visceral pain has its substrate in the viscerosomatic and musculosomatic convergence onto dorsal horn neurons.

WIND UP
Wind-up is a progressive, frequency-dependent

facilitation of the responses of a neurone observed on the application of repetitive (usually electrical) stimuli of constant intensity. The phenomenon of wind-up was first described by Lorne Mendell as a frequency-dependent facilitation of spinal cord neuronal responses mediated by afferent C-fibres. Mendell suggested that this phenomenon may be due to a reverberatory activity evoked by afferent C-fibres in interneurones of the spinal cord lasting for 2-3 s. If in this period of time another stimulus arrives to the cord, it sums with the ongoing activity to produce a more intense discharge in the interneurones than the one

 The observation that there were prolonged increases in

the excitability of dorsal horn neurones subsequent to the application of a wind-up evoking stimulus (Cervero et al., 1984; Cook et al., 1987).
This led to the proposal (Cook et al., 1987; Dickenson,

1990) that there was a causal relationship between wind-up and the hyperexcitability of spinal cord nociceptive neurones observed after peripheral damage known as `central sensitisation.
The blockade of the N-methyl-D-aspartate (NMDA)

subtype of glutamate receptors inhibited the generation of windup.

 3. COMPLEX NEURONS: less well-studied

group of dorsal horn neurons and are typically located in lamina VII. It is believed that these cells function in the integration of somatic and visceral afferent activity.

ASCENDING SPINAL TRACTS

 Dorsal horn nociceptive input is conveyed to supraspinal

centers by projection neurons extending through following ascending pathways:

(A) NEOSPINOTHALAMIC PATHWAYS SPINOTHALAMIC PATHWAY (B) PALEOSPINOTHALAMIC PATHWAY SPINORETICULAR PATHWAY SPINOCERVICOTHALAMIC PATHWAY SPINOTECTAL PATHWAY SPINOHYPOTHALAMIC PATHWAY

 Anatomically, axons from second-order neurons in the

supercial dorsal horn (laminae I and II) are segregated from those of deeper laminae (lamina V).
This provides anatomical separation between the

neospinothalamic (NSTT) and paleo-spinothalalmic (PSTT) tracts.

While both the NSTT and PSTT may be considered

labeledlines for the transmission of pain signals, the differential localization of NS neurons to laminae I and II, in contrast to a greater abundance of WDR neurons in lamina V, subserves functional distinctions in the type of nociceptive information that is transmitted in these pathways.

 The NSTT projects directly to the ventroposterior lateral

(VPL) nuclei of the thalamus and is composed predominately of NS neurons from lamina I and II (Kenshalo et al., 1980).
WDR neurons are in smaller numbers within these

laminae, and they comprise only a minority of NSTT bers.

NS neurons receive almost completely homogeneous

input from A-delta and high-threshold polymodal C-ber afferents, and encode stimulus localization and modality.
Therefore, the main role of the NSTT appears to involve

transmission of these signal qualities to the thalamus

 The PSTT is composed of axons from second-order

neurons arising in lamina II and V of the spinal cord. WDR neurons constitute the majority of cells from this lamina, with only a smaller number of NS neurons contributing to the axonal pool of the PSTT. Given the role of lamina V WDR neurons to encode noxious stimulus intensities, the co-localized transmission of both nociceptive and non-nociceptive afferent information within the PSTT appears to serve a stimulus discriminatory function. Unlike the NSTT, the PSTT is not a direct thalamic pathway. PSTT bers project to several supraspinal sites that are involved in (nociceptive) sensory processing and that exert pain modulatory control.

Tract of Lissauer
It is a small strand situated in relation to the tip of

the posterior column close to the entrance of the posterior nerve roots. It contains centrally projecting axons carrying discriminative pain and temperature information (location, intensity and quality), which enter the spinal column ascend or descend one or two spinal segments in this tract before penetrating the grey matter of the dorsal horn where they synapse on second-order neurons. The axons of these second-order neurons cross the midline and ascend in the anterolateral quadrant of the contralateral half of the spinal cord, where they join the spinothalamic tract.

 It consists of fine fibers which do not receive their myelin

sheaths until toward the close of fetal life. In addition it contains great numbers of fine nonmyelinated fibers derived mostly from the dorsal roots but partly endogenous in origin. These fibers are intimately related to the substantia gelatinosa.

 The spinothalamic tracts consist of second-order

neurones which convey pain, temperature, coarse (nondiscriminative) touch and pressure information to the somatosensory region of the thalamus. Axons arise from neurones in diverse laminae in all segments of the cord. Tract fibres decussate in the ventral white commissure. Pain and temperature fibres do so promptly, within about one segment of their origin, whilst fibres carrying other modalities may ascend for several segments before crossing. Spinothalamic fibres mostly ascend in the white matter ventrolateral to the ventral horn, partly intermingled with ascending spinoreticular fibres and descending reticulospinal fibres. Some authorities describe two spinothalamic tracts (lateral and ventral) with more-or-less distinct

 The lateral spinothalamic tract is sited in the lateral

funiculus, lying medial to the ventral spinocerebellar tract. Clinical evidence indicates that it subserves pain and temperature sensations. The ventral spinothalamic tract lies in the anterior funiculus medial to the point of exit of the ventral nerve roots and dorsal to the vestibulospinal tract, which it overlaps. On the basis of clinical evidence, it subserves coarse tactile and pressure modalities. A dorsolateral spinothalamic tract has been described in animals, arising mainly from lamina I neurones whose axons cross to ascend in the contralateral dorsolateral funiculus. These neurones respond maximally to noxious, mechanical and thermal cutaneous stimuli. That such a projection exists in man is suggested by examples of clinical pain relief following dorsolateral cordotomy.

 On reaching the lower brain stem, spinothalamic tract axons

separate. Axons in the ventral tract join the medial lemniscus. Axons in the lateral tract continue as the spinal lemniscus. There is clear somatotopic organization of the fibres in the spinothalamic tracts throughout their extent. Fibres crossing at any cord level join the deep aspect of those that have already crossed, which means that both tracts are segmentally laminated . Somatotopy is maintained throughout the medulla oblongata and pons. In the midbrain, fibres in the spinal lemniscus conveying pain and temperature sensation from the lower limb extend dorsally, while those from the trunk and upper limb are more ventrally placed. Both lemnisci ascend to end in the thalamus.

 On the basis of laminar site, functional properties, and

specific thalamic termination of their axons, spinothalamic tract neurones may be divided into three separate groups.

These are the: apical cells of the dorsal grey column (lamina I), deep dorsal column cells (laminae IV-VI), and

cells in the ventral grey column (laminae VII, VIII).

 Lamina I cells which project to the thalamus show

the following characteristics: In essence they respond maximally to noxious or thermal cutaneous stimulation, and consist mainly of high-threshold, but also some wide-dynamic-range, units. Their receptive fields are usually small, representing a part of a digit or a small area of skin involving several digits. Lamina I spinothalamic tract neurones receive input from A and C fibres. Lamina I spinothalamic tract neurones project preferentially to the ventroposterolateral nucleus of the thalamus, with limited projections to the

 The population of deep dorsal column (laminae IV-VI)

spinothalamic neurones contains wide-dynamic-range (60%), high-threshold (30%), and low-threshold (10%) type units. They can code accurately both innocuous and noxious cutaneous stimuli. Laminae IV-VI spinothalamic tract units project either to the ventroposterolateral (VPL) nucleus or to the centrolateral nucleus of the thalamus, and sometimes to both. Units projecting to the ventroposterolateral nucleus receive input from all classes (A, A and C) of cutaneous fibres.

 Ventral grey column (laminae VII and VIII) spinothalamic

tract cells respond mainly to deep somatic (muscle and joint) stimuli, but also to innocuous and/or noxious cutaneous stimuli. Cells of this group, which project exclusively to the medial thalamus, receive input from A, A and C classes of afferent fibres, and many respond to convergent input from receptors of deep structures. This population of neurones contains wide-dynamic-range (25%), high-threshold (63%), and low-threshold or deep (12%) units. Most of the spinothalamic tract cells in the ventral grey column project to the intralaminar nuclei of the thalamus. Wide-dynamic-range type neurones are particularly effective for discriminating between different intensities of painful stimulation. It has been suggested that the spinothalamic projection to the ventroposterolateral nucleus is concerned with the discriminative aspects of pain perception, whereas

SPINORETICULAR PATHWAYS
Spinoreticular fibres are intermingled with those of the

spinothalamic tracts, and ascend in the ventrolateral quadrant of the spinal cord. Evidence from animal studies suggests that cells of origin occur at all levels of the spinal cord, particularly in the upper cervical segments. Most neurones are in lamina VII, some are in lamina VIII, and others are in the dorsal horn, especially lamina V. Most axons in the lumbar and cervical enlargements cross the midline, but there is a large uncrossed component in cervical regions. Spinoreticular neurones respond to inputs from the skin or deep tissues. Innocuous cutaneous stimuli may inhibit or excite a particular cell, whereas noxious stimuli are often excitatory.

 It terminates in the brainstem at the medullary-

pontine reticular formation.

Information is sent from there to the intradmedian

nucleus of the thalamic intralaminar nuclei.

The thalamic intralaminar nuclei project diffusely to

entire cerebral cortex where pain reaches conscious level and promotes behavioral arousal.

Spinocervicothalamic pathway
Lesser contributions to nociceptive transmission are

made from neurons located in laminae III and IV of the dorsal horn, which project axons through the spinocervical tract and the postsynaptic dorsal column pathway, which both relay impulses indirectly to the thalamus through the lateral cervical nucleus and the dorsal column nuclei, respectively.

SPINOTECTAL PATHWAY
Spinotectal projections terminate within the tectum and

periaqueductal gray (PAG) region of the midbrain. Sinotectal tract neurons are of low-threshold, widedynamic-range, or high-threshold classes. Their receptive fields may be small, or very complex and encompass large surface areas of the body. They are likely to be involved in the motivationalaffective component of pain. Electrical stimulation of their site of termination in the periaqueductal grey matter results in severe pain in man.

SPINOHYPOTHALAMIC PATHWAY
More recently, a direct projection transmitting primarily

nociceptive information from the dorsal horn to the hypothalamus has been discovered. This is the spinohypothalamic tract, which provides an additional alternative route of activating the motivational component of pain and initiating neuroendocrine and autonomic responses. In fact, most SHT neurons (60%) project to the contralateral medial or lateral hypothalamus and, therefore, are presumed to have a considerable role in autonomic and neuroendocrine responses to painful stimuli. Therefore, the SHT appears to form the anatomic substrate that coordinates reflex autonomic reactions to painful stimuli. Some of the connections of SHT, for example, to the suprachiasmatic nucleus that partly controls the sleep/wake

INTRODUCTION
The trigeminal system receives afferent input from the

three divisions of the trigeminal nerve (i.e., ophthalmic, maxillary, and mandibular) that serve the entire face as well as the dura and the vessels from a large portion of the anterior two thirds of the brain. The trigeminal system has three sensory nuclei, all of which receive projections from cells that have cell bodies located within the trigeminal ganglion, a structure similar to DRG. Major transmitters of painful stimuli within the mouth and orofacial complex are the free nerve endings from the trigeminal nerve. Peripheral afferents from the trigeminal are thought to react to specific noxious stimuli and respond to

TRIGEMINAL GANGLION
The trigeminal ganglion (or Gasserian ganglion,

or semilunar ganglion, or Gasser's ganglion) is a sensory ganglion of the trigeminal nerve (CN V) that occupies a cavity (Meckel's cave) in the dura mater, covering the trigeminal impression near the apex of the petrous part of thetemporal bone. The trigeminal ganglion is a main generator of information from the orofacial complex in the human as well as in different types of mammals. Just like cells within the dorsal root ganglia of the spinal cord, cells in the trigeminal ganglion possess peripheral and central processes.

 The peripheral processes of trigeminal ganglion

neurons distribute to pain and temperature receptors on the face, forehead, mucous membranes of the nose, anterior two-thirds of the tongue, hard and soft palates, nasal cavities, oral cavity, teeth, and portions of cranial dura. The central processes enter the brain at the level of the pons (this is where all trigeminal sensory fibers enter the brain stem and where trigeminal motor fibers leave the brain stem). These central processes of trigeminal ganglion neurons conveying pain and temperature descend in the brain stem and comprise the SPINAL TRACT V. Fibers of spinal tract V terminate upon an adjacent cell group called the SPINAL NUCLEUS V, which forms a long cell column medial to spinal tract V (spinal tract and nucleus V form a slight elevation on the lateral

 On entering the pons, the fibres of the sensory root of the

trigeminal nerve run dorsomedially towards the principal sensory nucleus, which is situated at this level. Before reaching the nucleus ,50% of the fibres divide into ascending and descending branches - the others ascend or descend without division. The descending fibres, of which 90% are less than 4 m in diameter, form the spinal tract of the trigeminal nerve, which reaches the upper cervical spinal cord. The tract embraces the spinal trigeminal nucleus. There is a precise somatotopic organization in the tract. Fibres from the ophthalmic root lie ventrolaterally, those from the mandibular root lie dorsomedially, and the maxillary fibres lie between them. The tract is completed on its dorsal rim by fibres from the sensory roots of the facial, glossopharyngeal and vagus nerves. All of these fibres synapse in the nucleus caudalis.

 We are particularly concerned with the caudal most

portion of spinal nucleus V, because ALL of the PAIN and TEMPERATURE fibers from the face terminate in this caudal region of the nucleus (known as SUBNUCLEUS CAUDALIS). The other 2 parts of spinal nucleus V are the subnucleus oralis (which is most rostral and adjoins the principal sensory nucleus); the subnucleus interpolaris. The structure of the subnucleus caudalis is different from that of the other trigeminal sensory nuclei. It has a structure analogous to that of the dorsal horn of the spinal cord, with a similar arrangement of cell laminae. Cutaneous nociceptive afferents and small-diameter muscle afferents terminate in layers I, II, V and VI of

 Many of the neurones in the subnucleus caudalis that

respond to cutaneous or tooth-pulp stimulation are also excited by noxious electrical, mechanical or chemical stimuli derived from the jaw or tongue muscles. This indicates that convergence of superficial and deep afferent inputs via WDR or NS neurones occurs in the nucleus. Similar convergence of superficial and deep inputs occurs in the rostral nuclei and may account for the poor localization of trigeminal pain, and for the spread of pain, which often makes diagnosis difficult. Cells within spinal nucleus V possess axons that curve medially to CROSS the midline and course rostrally close to (but not as a part of) the medial lemniscus. These crossed fibers retain their close association with the medial lemniscus as they ascend in the brain stem and are called the trigeminothalamic tract (TTT).

 Spinal tract and spinal nucleus V are not exclusively

associated with C.N. V., It is also associated with C.N.s VII (facial), IX (glossopharyngeal) and X (vagus). The pain and temperature fibers associated with C.N. VII innervate the skin of the external ear, the wall of the external auditory meatus and the outer surface of the tympanic membrane. These fibers are the peripheral processes of cells that lie in the GENICULATE ganglion (located in the facial canal). The central processes of these neurons enter the brain with C.N. VII (at pontine levels, caudal to the trigeminal), travel in spinal tract V and end in spinal nucleus V. The pain and temperature information is then conveyed rostrally in the TTT (trigeminothalamic tract) to reach the VPM, from which it is relayed to somatosensory cortex (areas 3,1 and 2).

 Like C.N. VII, C.N. IX is involved in the pain and

temperature innervation of the EAR.

In addition, C.N. IX conveys pain and temperature

from the posterior one-third of the tongue, the auditory tube and the upper part of the pharynx .
The cell bodies of these pain and temperature axons

associated with C.N. IX lie in the relatively small SUPERIOR GANGLION IX (located just outside of the jugular foramen).
The central processes of cells in the superior ganglion

enter the brain with C.N. IX (at the lateral medulla), then enter our friend spinal tract V and synapse in the caudal

 C.N. X innervates the

EAR (along with C.N.s VII and IX). In addition, pain and temperature from the lower pharynx, the larynx and the upper esophagus are conveyed by C.N. X. The cell bodies of these pain and temperature axons lie in the SUPERIOR GANGLION X (located just outside the jugular foramen). The central processes of cells in the superior ganglion X pass into the brain at the lateral medulla,

REMEMBER
Lesion of spinal tract V along its entire course (the pain

information never gets to the caudal spinal nucleus) results in IPSILATERAL deficits in pain and temperature from the face etc. Interruption of the trigeminothalamic tract, which is comprised of axons that have crossed the midline, results in deficits in pain and temperature on the contralateral side of the face etc. Spinal tract and nucleus V are present in the pons and medulla The cells of origin of spinal tract V lie in the trigeminal ganglion Axons in spinal tract V terminate in the spinal nucleus V Axons of cells within spinal nucleus V project to the contralateral VPM

AN INTERESTING CLINICAL OBSERVATION

Reports in the clinical literature note that vascular lesions

that interrupt the blood supply to the spinal nucleus and tract V in the medulla (for example a thrombosis of the posterior inferior cerebellar artery) sometimes are immediately followed by sharp stabbing pain in and around the eye and on the ipsilateral face (hyperalgesia). A possible explanation for this paradox is that the pain fibers are highly irritated before they die (spontaneous pain also sometimes occurs on the contralateral side of the body immediately following a lesion of the anterolateral system). Please remember that lesions of spinal tract and nucleus V can result in PAIN in the face (in addition to loss of

 Integration of pain in higher centers is complex and

poorly understood. At a basic level, the integration and processing of painful stimuli may fall into the following broad categories: Discriminative component: This component is somatotopically specific and involves the primary (SI) and secondary (SII) sensory cortex. This level of integration allows the brain to define the location of the painful stimulus. Integration of somatic pain, as opposed to visceral pain, takes place at this level. The primary and secondary cortices receive input predominantly from the ventrobasal complex of the thalamus, which is also somatotopicallyorganized.

 AFFECTIVE COMPONENT

The integration of the affective component of pain is

very complex and involves various limbic structures. In particular, the cingulate cortex is involved in the affective components of pain (i.e., it receives input from the parafascicular thalamic nuclei and projects to various limbic regions). The amygdala is also involved in the integration of noxious stimuli. MEMORY COMPONENTS Recent evidence has demonstrated that painful stimuli activate the CNS regions such as the anterior insula. MOTOR CONTROL AND PAIN The supplemental motor area is thought to be involved in the integration of the motor response to pain.

THALAMUS

THALAMIC NUCLEI ASSOCIATED WITH PAIN

A. VENTRAL POSTERIOR NUCLEUS (VP)

B. INTRALAMINAR THALAMIC NUCLEI

C. MEDIALIS DORSALIS

VENTRAL POSTERIOR NUCLEUS

The ventral posterior (VP) nucleus is the principal

thalamic relay for the somatosensory pathways. It is thought to consist of two major divisions, the ventral posterolateral (VPl) and ventral posteromedial (VPm) nuclei. The VPl nucleus receives the medial lemniscal and spinothalamic pathways, and the VPm nucleus receives the trigeminothalamic pathway. There is a well-ordered topographic representation of the body in the ventral posterior nucleus. The VPl is organized so that sacral segments are represented laterally and cervical segments medially. The latter abut the face area of representation (trigeminal territory) in VPm.

 There is evidence that spinothalamic tract neurones

carrying nociceptive and thermal information terminate in a distinct nuclear area, identified as the posterior part of the ventral medial nucleus (VMpo). The VP nucleus projects to the primary somatic sensory cortex (SI) of the postcentral gyrus and to the second somatic sensory area (SII) in the parietal operculum. VMpo projects to the insular cortex.

INTRALAMINAR TALAMIC NUCLEUS

The term intralaminar nuclei refers to collections of

neurones within the internal medullary lamina of the thalamus. Two groups of nuclei are recognized. The anterior (rostral) group are subdivided into central medial, paracentral and central lateral nuclei. The posterior (caudal) intralaminar group consists of the centromedian and parafascicular nuclei. The central lateral nucleus receives afferents from the spinothalamic tract. central lateral nucleus projects mainly to parietal and temporal association areas.

MEDIALIS DORSALIS NUCLEI

The medial dorsal nucleus is the only nucleus in the

medial group, and it receives two kinds of inputs. Part of this nucleus receives pain afferents from the LSTT and the TTT, projects to the frontal lobe, and is involved in the response to pain. The other part of MD receives olfactory inputs from primary olfactory cortex. This nucleus is unique because it receives these olfactory inputs after they have been to cortex, and then relays them to insular and orbitofrontal cortex for associative olfactory functions.

 The thalamus is a complex structure that acts as the

relaying center for incoming nociceptive stimuli. The NSTT and PSTT project to different regions within the thalamus. NSTT neurons project to a caudal area of the ventroposterior lateral nucleus (VPLc). Nociceptive inputs from the NSTT are arranged in columnar zones that are somatotopically organized. Thalamic neurons within these zones retain many response characteristics of WDR and NS units. Thalamic wide-range neurons have centersurround receptive elds with distinct, small areas sensitive to low threshold excitation and a broad area that is excited by high-threshold nociceptive input. Thalamic NS neurons, like their spinothalamic counterparts, have smaller receptive elds that are excited by high intensity mechanical or thermal input.

 Both WDR and NS neurons of the VPLc summate

responses as a function of stimulus frequency and intensity. The PSTT projects to the intralaminar thalamic nuclei, the dorsal nucleus centralis lateralis, and medialis dorsalis. Most of the neurons within these thalamic areas are of the wide range type, sensitive to both nociceptive and non-nociceptive activation and with extensive overlapping input from cutaneous and visceral innervation. These units do not have the adaptive properties of neurons of the VPLc; intralaminar neurons summate responses, but response patterns do not reect direct spatial or temporal transformation of increments in stimulus frequency or intensity. Unlike neurons of the VPLc, intralaminar neurons

CORTICAL PROJECTIONS
Neurons from the NSTT project to the VPLc of the

thalamus; thalamo-cortical bers from this region terminate in S-I (and to a lesser extent S-II areas) of the somatosensory cortex. Thalamo-cortical bers from the intralaminar, lateral, and medial dorsal nuclei, driven by the PSTT, project more diffusely, with a smaller number terminating in S-I, while the majority project bilaterally to S-II. The somatotopic organization of the thalamus is preserved in S-I and to some extent SII; nociceptive input contributes to distinct regions of somatosensory activation within the cortex. There are projections from S-II to the anterior cingulate via the insula and to the posterior cingulate through a

 The role of the anterior cingulum in pain sensation and

pain related behavioral responses is such that the superior, anterior cingulate is commonly referred to as the nociceptive cingulate area (NCA). Anterior cingulate hypothalamic projections mediate components of neuroendocrine and autonomic responses to pain sensation.

GENERAL CHARACTERISTICS
It is well established that the brainstem has a significant

role in regulating pain-related signals at the spinal cord level. It has been commonly considered that brainstem -spinal pathways predominantly inhibit pain. However, there is accumulating evidence indicating that descending pathways also have pain facilitatory effects.

(A) Development and Modulatory Properties of Descending Inhibitory Controls

Descending pain inhibitory controls are immature at birth

and do not become functionally effective until postnatal day 10, although all descending projections are already present at birth. With advanced age the function of descending pain inhibition is impaired and this is associated with a loss of noradrenergic and serotoninergic fibers in the spinal dorsal horn. Conditioning noxious stimulation, which presumably activates descending pain modulatory pathways, has induced a weaker pain suppressive effect in females than in males (Staud et al., 2003) suggesting that descending inhibitory controls may have gender-specific

 Although the somatotopic organization of descending

inhibitory influence is quite diffuse, a preferential ipsilateral antinociception induced by electrical stimulation of the midbrain periaqueductal gray (PAG) indicates that the descending inhibitory effect may not be equally distributed throughout the body. (B)SPINAL MECHANISM MEDIATING THE DESCENDING PAIN INHIBITORY ACTION
A number of mechanisms are involved in mediating the

descending inhibitory effect at the spinal dorsal horn level.

Direct (postsynaptic) inhibition of spinal pain-relay neurons.

 Descending axon terminals have direct contacts with

presumed pain-relay neurons of the spinal dorsal horn, electrical stimulation of the brainstem induced inhibitory postsynaptic potentials in nociceptive neurons of the spinal dorsal horn and and spinal application of noradrenaline, a transmitter released from descending axons, hyperpolarized a population of nociceptive spinal neurons (North and Yoshimura, 1984).

These findings indicate that neurotransmitters released

from descending axons may block the ascending pain signal by producing a hyperpolarization of spinal relay neurons (direct postsynaptic inhibition).

Indirect inhibition of spinal pain relay neurons through activation of inhibitory interneurons.

 Superficial laminas of the spinal dorsal horn have a

population of interneurons containing inhibitory neurotransmitters such as -aminobutyric acid (GABA), glycine and enkephalin (Ruda et al., 1986). Descending pathways excite some of these putative inhibitory interneurons of the spinal dorsal horn (Millar and Williams, 1989) and this provides one more mechanism for descending inhibition of spinal painrelay neurons (indirect inhibition via excitation of inhibitory interneurons)

A hypothetical scheme for volume transmission of an inhibitory neurotransmitter from the descending axons to central terminals of nociceptive primary afferent nerve fibers (presynaptic inhibition of nociceptive afferent barrage to the spinal cord).

 Descending pathways may also suppress nociceptive

signals due to action on central terminals of primary afferent fibers (presynaptic inhibition). Accordingly, central terminals of nociceptive primary afferents have receptors for neurotransmitters released in the spinal cord only by descending axons, such as noradrenalin. In line with this, postsynaptic responses evoked by dorsal root stimulation in a population of lamina II neurons of the spinal dorsal horn were reduced by noradrenaline, without influence on direct activation of the same neurons by excitatory amino acids (Kawasaki et al., 2003). Due to rareness of axo-axonic synapses between nociceptive primary afferent nerve fibers and central neurons, it has been proposed that volume transmission may play a major role in presynaptic inhibition of nociception in the spinal dorsal horn (Rudomin and Schmidt, 1999); i.e.

(C) Physiological Significance of Descending Pain Inhibition

Descending pain inhibitory pathways have an important

role in the ascendingdescending circuitry, providing negative feedback control of nociceptive signals at the spinal cord level (Fields and Basbaum, 1999); i.e. a painful stimulus activates brainstem nuclei involved in descending antinociception and prevents excessive pain by attenuating the successive painful signals. This implies that a full activation of descending inhibition is observed only under painful conditions. The activation of descending inhibitory controls by a painful stimulus may not only serve reduction of excessive pain by negative feedback but it may also

 Importantly, analgesia induced by some centrally acting

drugs involves activation of descending pain inhibitory pathways (e.g. morphine).

(D)DESCENDING PAIN INHIBITION UNDER PATHOPHYSIOLOGIC CONDITIONS Pathophysiological conditions may cause complex changes in descending pain regulatory circuitry. Descending inhibition was stronger following inflammation as indicated by enhanced spinal antinociceptive effect by midbrain stimulation in inflamed animals (Morgan et al., 1991). Inflammation has been associated with increased turnover of noradrenaline (Weil-Fugazza et al., 1986) and increased number of alpha 2 adrenoceptors in the spinal cord (Brandt and Livingston, 1990).

 These changes are likely to contribute to an increase in

descending pain inhibition, and they probably explain the enhanced antinociceptive potency of spinally administered alpha 2-adrenoceptor agonists in inflamed conditions. Additionally, nerve injury or inflammation may activate descending facilitation. Increased inhibitory controls potentially help to maintain the capacity to use an inflamed body part for flight or fight in case of emergency, whereas decreased inhibition or increased facilitation of pain might in some cases help the healing process by promoting immobilization and protection of the injured region. However, a prolonged decrease of pain inhibition or increase of pain facilitation may not serve any useful purpose, but they just cause unnecessary suffering and

 Motor control and pain regulatory systems share many

common neurotransmitters. Disorders of neurotransmitter systems in the motor control circuitries of the basal forebrain are quite common and they are known to be associated with motor dysfunction such as in Parkinsons disease. In analogy, it may be proposed that similar disorders of neurotransmitter systems potentially occur also in pain regulatory circuitries and can underlie some chronic pain conditions by causing hypofunction of descending inhibitory controls. This possibility is supported by a recent series of studies indicating that striatal dopamine D2 receptor binding potential is associated with the occurrence of chronic orofacial pain as well as baseline pain sensitivity (Hagelberg et al., 2004); i.e. hypofunction of the nigrostriatal dopamine system may cause not only motor disorders but also chronic pain.

(E)DNIC (DIFFUSE NOXIOUS INHIBITORY CONTROL)

The application of conditioning noxious stimulation to one

area of the body is capable of inhibiting responses of the presumed pain-relay neurons of the spinal dorsal horn evoked by stimulation of other body areas. This implies that painful stimulation inhibits concurrent pain signals evoked from heterotopic stimulation sites allowing focusing of the sensory system on the most dangerous stimulus; this mechanism is called diffuse noxious inhibitory controls (DNIC) (Le Bars et al., 1979a,b). Although DNIC involves a descending inhibitory influence, it has been postulated that the net effect of DNIC is facilitation of pain perception evoked by the most threatening noxious stimulus; i.e. the strongest painful stimulus may become

 In line with this, the caudal

brainstem area implicated in descending inhibition of heterotopic nociceptive signals (i.e. involved in DNIC), the dorsal reticular nucleus of the medulla (Bouhassira et al., 1992), was shown to have a descending pronociceptive action on spinal nociceptive transmission mediated by homotopic neurons. Counter-irritation phenomena, including

(F)CLINICAL MANIPULATION OF DESCENDING INHIBITORY SYSTEM

Stimulation of descending inhibitory systems has been

used for treatment of various pain syndromes. This treatment method is based on the fact that the amygdala(PAG)rostral ventromedial medulla (RVM)dorsal horn endogenous antinociceptive system is endowed with high concentrations of opioid receptors in every relay station. E.G. TENS cause endorphin release which in turn activate the descending inhibitory system.

(A) PAG-RVM SYSTEM-CIRCUITERY IN MIDBRAIN AND MEDULLA

The PAG matter, located in the mesencephalon around

the Sylvius aqueduct was the first brain area shown to exert a powerful pain inhibitory action (Reynolds, 1969) and its pain modulatory role has been exhaustively studied.

 The lack of a strong projection from the PAG to the

spinal cord led to the discovery of a relay, the RVM, through which the PAG influences spinal nociception.
Both the PAG and RVM receive direct projections from

the spinal dorsal horn and, thus, they may control the ascending nociceptive input by a feedback mechanism.
The RVM includes the nucleus raphe magnus and

adjacent reticular formation, including the nucleus gigantocellularis pars a and paragigantocellularis ventralis, all of which project directly to the spinal cord.

 Based on their physiological response properties,

spinally projecting RVM neurons can be classified into three types: 1) On cells that give an excitatory response to a noxious stimulus starting just prior to a spinal nocifensive reflex. 2) Off cells that give an inhibitory response to a noxious stimulus starting just prior to a spinal nocifensive reflex. 3) Neutral cells that give variable responses or are unresponsive to noxious stimuli (Fields et al., 1991). Both on and off cells are activated by electrical stimulation of the PAG. Importantly, morphine applied systemically or in the PAG suppresses on-cell activity, increases off-cell

The typical firing patterns of RVM On, Neutral and Off cells just prior to nociceptive withdrawal of the tail in response to noxious heat. On cells accelerate firing, neutral cells show no discernible change in activity, and Off cells show a pause in activity immediately before the reflex response

 Additionally, morphine administered into the RVM

suppresses directly on but not off cell activity . Morphine-induced increase of off-cell activity is indirect through a GABAergic mechanism within the RVM. These findings suggest that on and off cells of the RVM and supraspinal opioid receptors have an important role not only in antinociception induced by administration of morphine but also in general in descending inhibitory controls relaying through the PAG and RVM. The pain modulatory role of neutral cells of the RVM is less clear. It is known that a subgroup of neutral cells are serotoninergic (Mason, 1997); serotoninergic RVM cells project to the spinal cord (Lakos and Basbaum, 1988) and spinal serotonin receptors

 Serotoninergic neutral cells possibly contribute to spinal

antinociceptive action by modulating the effects induced by on and off cells.

(B)PAG-RVM SYSTEM-CIRCUITERY AT SPINAL CORD LEVEL

The dorsolateral funiculus is the main

descending pathway mediating antinociceptive effects from the RVM to the spinal dorsal horn (Basbaum et al., 1976). A number of neurochemical and neurophysiological mechanisms contribute to spinal antinociceptive effect induced by stimulation of the PAG or RVM: (i) Among the pain inhibitory neurotransmitters are monoamines, amino acids and neuropeptides. (ii) Among the neurophysiological inhibitory mechanisms at the spinal cord level are postsynaptic inhibition of pain-relay neurons (Giesler et al., 1981), activation of inhibitory interneurons (Millar and Williams, 1989) and presynaptic inhibition of afferent barrage from the primary

 It should also be

noted that the activation of the PAG RVMspinal cord pathway might recruit other parallel descending pain inhibitory pathways.
Namely, the

association of the antinociception induced by PAG stimulation with a spinal release of noradrenaline (Cui et

(C)PAG-RVM SYSTEM-CONVERGENCE FROM OTHER PAIN MODULATING AREAS

A large number of brainstem, diencephalic (thalamic and

hypothalamic) and telencephalic (cortical and subcortical) structures suppress pain through descending projections to the spinal dorsal horn, and in most cases their descending pain suppressive effect is relayed through the PAG and the RVM [e.g. the ventrolateral orbital cortex (Dong et al., 1999), prefrontal cortex (Hardy, 1986), amygdala (Helmstetter et al., 1998), parafascicular thalamic nucleus (Sakata et al., 1989) and lateral hypothalamus (Aimone and Gebhart, 1988)]. These findings suggest that the RVM is the final relay station for descending antinociceptive action from

 Amygdala plays an important role in emotional behavior.

Nociceptive inputs through the spinoparabrachio

amygdala pathway probably contribute to paininduced changes in affective behavior (Bernard et al., 1996) and the projections of the amygdala to the PAGRVM circuitry may be involved in mediating the influence of emotions on pain (Helmstetter et al., 1998).
Stressful situations like physical exercise, exposure

to extreme temperatures, fight, fear and pain may induce a decrease in pain sensitivity (Amit and Galina, 1986; Terman and Bonica, 2001), a phenomenon called stress induced analgesia(SIA).

 Stress activates the hypothalamo pituitaryadrenal

axis by releasing the corticotrophin releasing factor in the hypothalamus (Lariviere and Melzack, 2000) and this may result in modulation of pain due to endocrine mechanisms. Alternatively or in parallel, stress may induce spinal antinociception through axonal projections from the hypothalamus to the PAGRVM circuitry. Lesions of the dorsolateral funiculus attenuate both opioid and non-opioid forms of stress-induced analgesia indicating that descending medullo-spinal pathways have a significant role in mediating the spinal antinociceptive action induced by stress.

 In general, less severe stressors are thought to

activate the endogenous opioid system and elicit the opioid-mediated form of stress-induced analgesia. On the other hand, more severe stressors recruit pain inhibitory mechanisms that are independent of the endogenous opioid system (Akil et al., 1986; Amit and Galina, 1986; Butler and Finn, 2009; Mogil et al., 1996). For example, a 3-min swim in warm water (32 C) elicits antinociception that is mediated by the endogenous opioid system because this form of antinociception is blocked by naloxone, a non-selective opioid receptor antagonist. On the other hand, swim in cold water (2 C for 3.5 min) elicits antinociception that is not affected by low doses of naloxone that inhibit morphineinduced

(D)NORADRENERGIC PAIN MODULATION:NA BRAINSTEM NUCLEI

Noradrenaline is known to have a significant

antinociceptive influence through action on spinal alpha2-adrenoceptors (Yaksh, 1985). The source of spinal noradrenaline is descending axons originating in the noradrenergic neuronal cell groups of the brainstem particularly the locus coeruleus (or A6) but also noradrenergic cell groups A5 and A7 . The locus coeruleus, A5 and A7 cell groups are connected with other paincontrol centers and all of them receive projections from the PAG. Additionally, the locus coeruleus receives projections from the central nucleus of the amygdala, preoptic area, paraventricular nucleus of the hypothalamus and lateral

 Of the nuclei projecting to

noradrenergic cell groups of the brainstem, the parabrachial nucleus is noteworthy since it is an important relay for nociceptive signals from the superficial laminas of the spinal cord to the amygdala and hypothalamus, structures involved in control of emotional responses and stress, respectively. A5 and A7 constitutes the lateral tegmental area and they project to thalamus and hypothalamus. The locus coeruleus (A6 cluster) which is distinct from lateral tegmental area innervates hippocampus, cerebral cortex,

(E) NORADRENERGIC PAIN MODULATION:SPINAL CORD LEVEL

Electrical stimulation of the noradrenergic locus

coeruleus/subcoeruleus, A5 and A7 cell groups produces spinal antinociceptive effects. Interestingly, activation of alpha2-adrenergic receptors within the noradrenergic cell groups of the brainstem has not produced marked antinociceptive effects ,but even hyperalgesia in some experimental conditions. These findings suggest that spinal and supraspinal alpha2-adrenoceptors may have opposite effects on pain sensitivity. At the spinal cord level, several pain inhibitory mechanisms may be activated by noradrenaline released from descending pathways.

 First, direct catecholaminergic innervation of the cell

bodies of spinothalamic tracts neurons provides a structural basis for postsynaptic noradenergic inhibition of spinal pain-relay neurons. Second, in the superficial laminas of the spinal dorsal horn noradrenaline activates a population of small, lowthreshold units that are likely to be inhibitory interneurons. Noradrenergic activation of inhibitory interneurons involves enhancement of GABAergic and glycinergic inhibitory synaptic transmission in the substantia gelatinosa. Third, noradrenaline inhibits transmission of nociceptive signals in the spinal cord due to action on presynaptic alpha2-adrenoceptors (particularly adrenoceptor subtype alpha 2A).

PHYSIOLOGICAL ROLE OF NONADRENERGIC PAIN MODULATION

The descending noradrenergic systems have a low tonic

activity, since alpha2-adrenoceptor antagonists or knockouts of various subtypes of alpha2-adrenoceptor have not consistently produced increases in pain-related responses to brief noxious stimuli in animals without sustained pain i.e. noradrenergic systems have little influence on baseline pain sensitivity. During persistent pain, however, noradrenergic systems have a more important role. This is shown by the findings that a lesion of the noradrenergic locus coeruleus (Tsuruoka and Willis, 1996) or a knockout of alpha- 2A adrenoceptors (Mansikka et al., 2004) significantly increased pain-related reflex responses in animals with inflammatory pain,

SUMMARY OF DESCENDING MODULATION OF PAIN

The magnitude of the ascending nociceptive signal and the

consequent pain sensation can be greatly influenced by descending pathways originating in the brainstem and terminating in the spinal dorsal horn. The bestknown descending circuitries involved in pain inhibition are the PAGRVMspinal cord pathway and the descending noradrenergic pathways. Descending painregulatory pathways are subject to bottom up (feedback inhibition) as well as top down control (e.g. cognitive and emotional regulation). The descending inhibitory effect is mediated by a number of neurotransmitters such as monoamines, peptides and amino acids, and by several different types of neurophysiological mechanisms acting on central terminals of primary afferent nociceptive nerve fibers, spinal interneurons and spinal projection neurons. In conditions that cause persistent pain, such as

SESITIZATION

One of the hallmarks of nociceptive pathways is sensitization in response to a damaging stimulus whereby the behavioral response to subsequent stimuli is enhanced. In some cases normally nonnociceptive stimuli elicit pain because of a decrease in threshold (allodynia); in others, a normally painful stimulus becomes even more painful (hyperalgesia). Two general mechanisms have been identied one acting at the periphery (peripheral sensitization) an the other acting centrally (central sensitization).