1. What is pain?
The "standard" definition of pain is that of the International Association for the Study of
Pain:-
This definition is extremely unfortunate. Definitions tend to force people into particular
ways of thinking. By concentrating on the subjective nature of pain, this definition allows
us to conveniently ignore individuals whose physical findings are all consistent with a
diagnosis of "pain", but who cannot relate a subjective feeling of pain. Indeed, it tells us
that (appearances to the contrary) such people are not in pain!
• Even more tellingly, we now have a fairly good "molecular memory for pain
stimulation". The gene c-fos is rapidly expressed in the spinal cord in response to painful
(but not to other) peripheral stimuli.
This is further evidence that we should not rely only on pain being "always subjective".
Pain is also something that can now be documented in a fairly objective fashion, albeit
only using fancy tools in the laboratory. Clinically it is still, and always will be vitally
important to listen to the patient who reports pain. But pain does not stop there. As Cross
[1994] has said:
"The affective-motivational aspects of pain originate in the periphery, and suffering is not
merely a matter for the neocortex; it is profoundly more ancient and primitive
phylogenetically and is reflected in fibre tracts and neural networks throughout the
nervous system".
Note that c-fos is a proto-oncogene, and is therefore likely to be involved in regulation of
major structural and functional changes in the cells where it is induced. We know that
volatiles and N2O are not adequate to suppress c-fos expression, and that opiates are not
as effective at this task as local or neuraxial block. Some evidence suggests that the latter
approaches are more effective in preventing chronic pain states.
We must also remember that although acute pain may have survival value (causing e.g.
removal of the injured limb from a harmful stimulus), chronic pain is of no value
whatsoever, and is indeed a major scourge of humanity.
2. Pain pathways.
Previously, pain pathways were seen as having three components:-
1. A first order neurone (cell body in dorsal root ganglion) which transmits pain
from a peripheral receptor to ..
2. A second-order neurone in the dorsal horn of the spinal cord, which axon crosses
the midline to ascend in the spinothalamic tract to the thalamus where..
3. A third-order neurone projects to the postcentral gyrus (via the internal capsule).
a. Peripheral receptors;
b. Neural pathways;
c. Spinal Cord mechanisms & long tracts;
d. Brainstem, thalamus, cortex & other areas.
e. Descending pathways.
a. Peripheral receptors
1. First pain
2. Second pain
It is important to realise that there are two distinct responses to a painful stimulus, a "first
pain" and a "second pain". The first pain is well-localised and brief, the second is more
diffuse and protracted.
First pain is described as sharp, and "pricking". It localises to a well-defined part of the
body surface.The receptors for this first pain are high threshold mechanoreceptors. There
appear to be specific "nociceptors" which mediate pain, and ONLY pain.
Second pain is due to stimulation of receptors that exist in many tissues (but not in,
paradoxically, the brain). It is often described as dull (i.e. not sharp) and aching. It is
poorly localised. Receptors for this second pain are termed polymodal nociceptors. This
pain tends to last beyond the termination of an acute painful stimulus. Sources, pathways,
perception of and treatment of the two types of pain are very different. Visceral pain is
predominantly of the "second pain" type.
Visceral pain can however sometimes be referred to a region of the body surface (for
example, shoulder tip pain with sub-diaphragmatic irritation). See [Cervero, F.
Physiological Rev 1994(74.1) 95-129pp] for a review of the sensory innervation of the
viscera.
In terms of pain perception, thresholds for feeling pain are remarkably constant from
individual to individual. i.e. Peripheral receptor stimulation of sufficient intensity will
reproducibly cause pain at the same level in most people. The response of the individual,
and his tolerance of the pain, will however differ markedly between individuals.
"First pain" responses are conveyed from the periphery to the dorsal horn of the spinal
cord in small myelinated fibres (A delta) while "second" pain is conveyed in non-
myelinated C fibres. This is important, especially when considering the "gate control
theory" detailed below. Also of importance to this theory are afferent stimuli coming in in
large myelinated fibres (A beta fibres), from peripheral vibration / pressure / touch
receptors.
1. initial connections : laminae in the spinal grey matter close to where the fibres
enter the spinal cord.
2. Local interconnections.
3. Ascending pathways and descending (control) pathways are considered much
later.
An important property of WDR neurons is "wind up". This occurs with repetitive
stimulation at about once per second via C fibres - each added stimulus increases the
response of the WDR cell. Wind-up is seen as a good justification for treating pain early
and well! Wind up may be related to stimulation of glutamate receptors (especially the N-
methyl D Aspartate or "NMDA" receptor, a receptor which is very topical at present)!
Many NMDA antagonists exist, but most have significant side effects (e.g. ketamine).
Clinically, evidence for wind-up has been hard to come by, although some recent studies
attest to the value of pre-emptive analgesia. See, for example, Mansfield(1996). Some
evidence suggests that mechanisms other than wind-up may be important in the
development of visceral pain, although the NMDA receptor appears to still be a major
player [J Physiol(Lond) Dec 1995 489(2) 545-55pp].
2. Spinal pathways: local interconnections. There are several. Of great importance are
connections mediating so-called "gating". The basic idea here is that "painful stimuli"
coming into the cord on C fibres can be modified by other inputs, which "close the gate
on the incoming pain". These inputs come from:
• A delta fibres;
• A beta fibres;
• others.
Mechanisms of inhibition in the dorsal horn may be very complex - incoming nociceptive
fibres express opioid receptors, opioids here blocking sP release, and they probably also
act post- synaptically. The presence of these opioid receptors at least partially explains
the potent effect of small doses of intrathecal opiates. In addition, GABA, somatostatin,
neurotensin, CCK and neuropeptide Y may play a role in pain transmission.
A wide variety of drugs has been used for "antinociception" at the spinal level, including
opioids, alpha-2 agonists, and local anaesthetics. Agents such as ketamine and
somatostatin may however be neurotoxic. Of interest is the potent analgesia induced by
spinal octreotide! [Rawal N, Ann Med Apr 1995 27(2) 263-8pp].
1. The old spino-reticulo-diencephalic pathway does just that - it mainly ends in the
reticular system of the brainstem, but also sends fibres to the thalamus (the medial nuclei
of the thalamus). Probably important are connections between the reticular system and
the hypothalamus (and thalamus) - these may explain autonomic components of the pain
response. ‘Emotional’/affective responses to pain may be explained by projections that go
from the medial nuclei of the thalamus to most of the cortex, especially the frontal areas,
and notably to the anterior cingulate gyrus! (In the bad old days people sometimes did
prefrontal lobotomies for intractable pain)! The basal ganglia may also be involved in
pain discrimination, the affective component of pain, and even in pain modulation
[Chudler E & Dong W, Pain 1995 60(1) 3-38pp].
2. The fresh, new "spinothalamic tract" nips up to the ventrobasal part of the lateral
thalamus. Connections go from here to the sensory cortex (postcentral gyrus), which
explains the precise localisation of somatic pain. It is obvious that this tract is NOT the
main pain pathway, because lesions along this pathway do not cancel out the sensation of
pain, and, in fact, may cause severe pain (the "thalamic syndrome" - possibly due to
damage to inhibitory pathways).
Positron emission tomography (PET) has been used to study the response to pain. Acute
traumatic nociceptive pain appears to activate the hypothalamus and PAG, but a whole
array of other areas also become involved (including the prefrontal cortex, insula, anterior
cingulate cortex, posterior parietal cortex, primary motor and somatosensory areas,
supplemental motor area and even the cerebellum. Further demonstration of the complex
nature of pain. [Pain Feb 1996 64(2) 303-14pp].
e. Descending pathways.
• Cortex;
• Thalamus;
• Brainstem, where the Periaqueductal grey matter (PAG) is particularly important.
1. Fibres pass from PAG to the reticular formation of the medulla (the nucleus raphe
magnus or "NRM", and the closely associated nucleus reticularis gigantocellularis
pars alpha, and nucleus reticularis paragigantocellularis, all together called the
ventromedian medulla or "VMM") where connections are serotoninergic, and
from there axons descend in the "dorsolateral funiculus" of the spinal cord, to end
up (surprise, surprise) on interneurones right next to the substantia gelatinosa
(lamina II) in the cord. The synapses here are enkephalinergic. Stimulation of this
system causes inhibition of incoming pain impulses. Thus, although serotonin
applied peripherally augments pain, its action centrally is important in descending
inhibition of incoming painful impulses! New evidence suggests that GABA is
also important in inhibition of pain pathways by the VMM [Neuroscience Jul
1996 73(2) 509-18pp].
2. To make matters more complex, quite apart from the above inhibitory pathway
that works mainly on opiates, there is a separate, noradrenaline-based pathway
that inhibits pain. Noradrenaline-based projections appear to come from the
NRM, and also from the locus coeruleus in the pons. This is one explanation why
antidepressants (which inhibit noradrenaline uptake) may be effective in
controlling pain, but remember that antidepressants also inhibit serotonin uptake,
so they may also increase activity in the fibres that pass from PAG to medulla!
Opioids inhibit "on" neurones and increase transmission in "off" neurones, and
noradrenaline also inhibits "on" neurons.
Opioids work in two main ways: they either block neurotransmitter release (by inhibiting
calcium influx into the presynaptic terminal), or hyperpolarise neurones by opening a
potassium channel (and therefore effectively temporarily knock the neurone out of
action)!
Corresponding (more-or-less) to the three receptor classes, there are three main groups of
endogenous opioids: the enkephalins, endorphins and dynorphins. Enkephalins act
mainly on delta receptors, dynorphins on kappa receptors, while beta endorphin acts on
both mu and delta receptors. Morphine is almost exclusively a mu agonist. Mu and delta
receptors appear to be expressed on the same cells, and stimulation of one receptor
increases the affinity of the other! Beta endorphin is also a "neurohormone" in that it may
have distant effects on neurones with mu receptors, after being released in the
hypothalamus.
The effect of opioids on the "on" and "off" cells in the medulla is most interesting:
ONLY the "on" cell is affected by opioids - it is inhibited, probably by hyperpolarization
due to opening of potassium channels. The "off" cell certainly becomes more active in the
presence of opioids, but this is only secondary to the lessened activity of the "on" cell.
The "on" cell is also inhibited by the alpha-2 agonist clonidine. In fact, in some cells the
mu receptor and the alpha-2 receptor are linked to the same G protein and the same
potassium channel! Of even more interest is evidence that by giving morphine we can
activate endogenous circuitry that turns on enkephalin release! See [Fields, Ann
Neurology, 1994 35 S42-45pp].
The roles of the various types of opiate receptor have recently been clarified by studies in
opiate receptor knockout mice. Mu-receptor knockout mice had shorter latencies on tail-
flick and hot plate tests, than did wild-type mice, and morphine did not reduce responses
to pain. These studies support the contention that the mu receptor is the main player in
morphine-induced analgesia. [Proc Natl Acad Sci U S A Feb 1997 94(4) 1544-9pp]
2. Cross, SA. Mayo Clin Proc1994 (69) 375-383. Pathophysiology of Pain. This
article on pain mechanisms is still by far the best summary we have encountered!
4. Mansfield MD. et al. BJA. 1996 (76) 358-361. Influence of dose and timing of
administration of morphine on postoperative pain and analgesic requirements.