Heat, Cold, and Pain

This page examines the detection of heat, cold, and pain.

Why pain? Because at least some of the receptors of heat and cold — when the
stimulus exceeds a certain threshold — transmit signals that the brain interprets as
pain.

The Receptors
Few, if any, of the receptors of heat, cold, and pain are specialized transducers (in
the way that, for example, the Pacinian corpuscle is). Rather they are sensory
neurons whose plasma membrane contains transmembrane proteins that are ion
channels that open in response to particular stimuli. A single neuron may contain
several types of these ion channels and thus be able to respond to several types of
stimuli. Like all sensory spinal neurons, their axons travel to a dorsal root ganglion
of the spinal cord, where their cell bodies reside, and then on in to the gray matter
of the spinal cord. [View]

Three types of sensory neurons are found in the skin.

 Aδ ("A-delta") fibers
o These are thinly-myelinated.
o They transmit signals in response to heat and touch. If the stimulus
exceeds a certain threshold, the brain interprets these as acute pain.
This is "good pain" because it warns you to do something to take care
of the problems, e.g., a hot saucepan.
 C fibers
o These are unmyelinated and thus conduct impulses slowly.

Link to a discussion of the role of myelin in speeding the conduction of

nerve impulses.

o C fibers also respond to heat and touch. If the stimulus exceeds a

certain threshold, the brain interprets these as diffuse, dull, chronic
pain. This is "bad pain" because it cannot be alleviated simply by
removing the stimulus. It is pain generated by such things as damaged
tissue or pain that remains after the stimulus that caused acute pain
has been removed.
 Aβ ("A-beta") fibers
o These are thickly-myelinated fibers.
o They mostly respond to painless stimuli such as light touch.

Heat
There are several types of ion channels in the skin that respond to temperature.
They are all transmembrane proteins in the plasma membrane that open to
let in both calcium ions and sodium ions (the latter the source of the action
potential). Between them, they cover a range of temperatures.

 TRPV4
Warm (~27–34°C)
 TRPV3
Warmer (~34–39°C)
 TRPV1
Hot (≥43°C). Also activated by capsaicin, the active ingredient of hot chili
peppers, by camphor, by acids (protons), and by pain-inducing products
of inflammation.
 TRPV2
Painfully hot (>52°C)

Knockout mice lacking the TRPV1 receptor not only do not avoid water with
capsaicin in it but have a diminished response to heat and to substances that normal
elicit itching.

Birds also have TRPV1 receptors. Theirs also respond to heat (and acids), but do
not respond to capsaicin. This must explain why birds happily eat hot chili peppers
(and so disperse their seeds).

The vampire bat, Desmodus rotundus, expresses normal TRPV1 receptors in the
sensory neurons leading to the dorsal root ganglia, and these respond normally to
painful heat (> 43°C). However, these bats express a shortened version of TRPV1
(produced by alternative splicing) in their trigeminal nerves that run from the bat's
upper lip and nose. The shortened receptors respond to a lower temperature
(~30°C) enabling the bats to detect the warmth radiating from the skin of their
victims.

Cold

Two candidate receptors:

 One, designated TRPM8, is a channel that admits Ca2+ and Na+ in response
to moderate cold (10–25°C) or menthol (the ingredient that gives mint its
"cool" touch and taste). Knockout mice lacking the gene encoding the
TRPM8 receptor do not avoid cold places as normal mice do.
 A second, designated TRPA1, responds to lower temperatures (<18°C). It
also responds to several irritant chemicals eliciting signals that the brain
interprets at pain. TRPA1 is found in the hair cells of the inner ear that
respond to sound and changes in position.) However, TRPA1 knockout
 mice respond normally to cold and seem to have normal hearing so the
precise role of these receptors is still uncertain for those stimuli.

TRPA1 channels serve a different function in pit vipers like rattlesnakes.

These cold-blooded animals detect warm-blooded prey using temperature-
sensitive neurons at the base of pits in their head. The neurons contain
TRPA1 channels that open wide when radiant heat entering the pit raises
their temperature above 27°C.

Pain

When sensory nerve fibers are exposed to extremes, they signal pain. Pain
receptors are also called nociceptors.

Processing Pathways
All the neurons in the skin are part of the sensory-somatic branch of the peripheral
nervous system. Their axons pass into the dorsal root ganglion, where their cell
body is located, and then on in to the gray matter of the spinal cord where they
synapse with interneurons. [View]

Several different neurotransmitters have been implicated in pain pathways. Three

of them:

 glutamate. This seems to be the dominant neurotransmitter when the

threshold to pain is first crossed. It is associated with acute ("good") pain.
 substance P. This peptide (containing 11 amino acids) is released by C
fibers. It is associated with intense, persistent, chronic — thus "bad" — pain.
 glycine. It suppresses the transmission of pain signals in the dorsal root
ganglion. Prostaglandins potentiate the pain of inflammation by blocking its
action.

Neuropathic Pain
This is pain caused by injury to the nerves themselves such as by mechanical
damage, massive inflammation, and growing tumors.

Visceral Pain
The brain can also register pain from stimuli originating in sensory neurons of
the autonomic nervous system. This so-called visceral pain is not felt in a discrete
location as pain signals transmitted by the sensory-somatic system are.

Treating pain with drugs

The weapons presently available to reduce pain are many in number but few in
types. They are

 Non-steroidal anti-inflammatory drugs (NSAIDs)

 Opioids

NSAIDs

Inflammation is caused by tissue damage and, among other things, causes pain.
Damaged tissue releases prostaglandins and these are potent triggers of pain.

Prostaglandins are 20-carbon organic acids synthesized from unsaturated fatty

acids.
Link to illustrated discussion.
There are at least three key enzymes that synthesize prostaglandins:

 Cyclooxygenase 1 (Cox-1)
 Cyclooxygenase 2 (Cox-2)
 Cyclooxygenase 3 (Cox-3)

Most NSAIDs block the action of all three cyclooxygenases. They include:

 aspirin
 ibuprofen (Advil®, Motrin®)
 naproxen (Aleve®)
 and many others

Two NSAIDs

 celecoxib (Celebrex®)
 rofecoxib (Vioxx®)

were introduced in 1999 that selectively inhibit Cox-2 while leaving Cox-1
untouched. It was hoped that these would provide pain relief without the
gastrointestinal side effects associated with the broad spectrum NSAIDs. However,
the manufacturer of Vioxx® removed it from the market on 30 September 2004
because it increases the risk of heart attacks and strokes.

Acetaminophen (Tylenol®)

This is also a nonsteroidal anti-inflammatory drug but its mode of action is

different from the others. It selectively inhibits Cox-3 and provides pain relief
without irritating the stomach. It is particularly useful for

 people allergic to aspirin and its relatives

  avoiding the risk of Reye's syndrome that has been associated with giving
aspirin to children with viral infections.

Opioids

Opioids are extremely effective pain killers

but are also addictive so their use is
surrounded by controversy and regulation.

Some examples:

 morphine
 codeine
 heroin
 methadone
 oxycodone

Opioids bind to receptors on interneurons in

the pain pathways in the central nervous
system. The natural ligands for these
receptors are two enkephalins — each a
pentapeptide (5 amino acids):

 Met-enkephalin (Tyr-Gly-Gly-Phe-
Met)
 Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu)

The two enkephalins are released at synapses on neurons involved in transmitting

pain signals back to the brain. Instead of synapsing with a dendrite or cell body, the
enkephalin synapse occurs close to the terminal of a pain-signaling neuron. The
enkephalins hyperpolarize the presynaptic membrane thus inhibiting it from
transmitting these pain signals.

The drawing shows how this mechanism might work. The activation of enkephalin
synapses suppresses the release of the neurotransmitter (substance P) used by the
sensory neurons involved in the perception of chronic and/or intense pain.

The ability to perceive pain is vital. However, faced with massive, chronic,
intractable pain, it makes sense to have a system that decreases its own sensitivity.
Enkephalin synapses provide this intrinsic pain-suppressing system.

Morphine and the other opioids bind these same receptors. This makes them
excellent pain killers.

However, they are also highly addictive.

  By binding to enkephalin receptors, they enhance the pain-killing effects of
the enkephalins.
 A homeostatic reduction in the sensitivity of these synapses compensates for
continued exposure to opioids.
 This produces tolerance, the need for higher doses to achieve the prior
effect.
 If use of the drug ceases, the now relatively insensitive synapses respond
less well to the soothing effects of the enkephalins, and the painful
symptoms of withdrawal are produced.

Prospects for future pain relievers

Research is progressing on coupling substance P to a cytotoxin.

The plan:

 Inject the conjugate into the cerebrospinal fluid so that it can

 bind to substance P receptors in the spinal cord and
 be taken in by endocytosis.
 Once inside, the toxin portion of the conjugate kills the cell
 thus interrupting the pathway that mediates chronic, intractable pain while
leaving untouched the "good pain" pathways.