Pain


Pain Afferents

Pain afferents can be myelinated or unmyelinated.

A C fiber can respond to a broad range of painful stimuli, including mechanical, thermal or metabolic factors. The pain produced is slow, burning, and long lasting. The neurotranmitter in the dorsal horn is glutamate along with certain peptides such as substance P. The receptors for glutamate are not only fast, five subunit ligand gated ion channels, but also NMDA receptors. The latter do not open immediately, but only following prolonged depolarization. Thus, continual stimulation of C fibers eventually causes greater excitation in the postsynaptic neurons in the dorsal horn as the NMDA receptors start adding to the response.

An A-delta fiber responds to either mechanical stimuli or temperature stimuli in the painful realm and produces the acute sensation of sharp, bright pain. Their neurotransmitter in the dorsal horn is glutamate acting on fast, five subunit ligand gated ion channnels.

The receptor for capsaicin, which is found in hot peppers, is located in the C fibers. This ion channel normally is opened by hot stimuli.

C fibers, Substance P and Inflammation

Interestingly, the C fibers interact with the process of inflammation. Observe the figure below. The directions that action potentials conduct should seem quite surprising, because action potentials in certain branches of an afferent neuron are moving peripherally!! The is called the axon reflex. In this way, certain painful stimuli not only lead to the sensation of pain in the central nervous system, but also to the release of substance P locally. This increases inflammation by causing histamine release and dilation of blood vessels.

Reduction in the Perception of Pain

One phenomenon you may have observed in yourself is that stimulation of touch sensors (A-beta fibers) in the skin by rubbing can disrupt the sensation of pain arising in a nearby structure such as a muscle. This is usually interpreted in terms of the gate control theory.

Observe the figure of the dorsal horn, which shows that large, mechanically sensitive afferents excite interneurons that in turn inhibit the neurons that carry pain information from the dorsal horns to the brain. (Axons in the anterolateral tract project to the thalamus.)

What physiological function this might serve is not clear, but it does help explain various phenomena that reduce pain. The effect of transcutaneous electrical stimulation (TENS) presumably is due to this effect. In these devices, weak electrical current is applied to the skin near the site of pain (such as the lower back) in order to stimulate the A-beta fibers and reduce the flow of pain information to the brain.


Much more potent, however, is the analgesia producted by morphine and other related opiates. The opiates bind to opioid receptors found in many areas of the brain, but are especially concentrated in the periaqueductal gray(ie; the area surrounding the cerebral aqueduct in the midbrain), the medulla and the dorsal horns. Infusion of morphine into the periaqueductal gray is especially effective in producing profound analgesia. This also is the area of the brain in which electrical stimulation produces a strong analgesic effect.

Naturally, with such a potent effect, one suspects that the brain contains molecules that naturally activate the receptors that respond to the opiates. These molecules are termed the opioid peptides, and include the enkephalins, dynorphin and beta-endorphin. Beta-endorphin is released by neurons with cell bodies in the hypothalamus and we won't consider this further.

The enkephalins (and dynorphin) are found in the periaqueductal gray, the medulla and the dorsal horns. Observe the pathway to the left that descends from the periaqueductal gray via the medulla to the dorsal horns. This leads to the release from interneurons of enkephalins that inhibit the flow of pain information to the brain.


Neuropathic Pain

The term neuropathic pain refers to pain that arises due to altered neuronal properties rather than an actual painful stimulus. On the other hand, nocioceptive pain refers to pain that arises due to a painful stimulation of pain afferent neurons. A table on the handout under disorders compares the clinical presentation of the two. There is no need to memorize this table, but do become familiar with the terminology used.

Consider these terms often connected to neuropathic pain:


What is meant by hyperalgesia?

Answer

What is meant by allodynia?

Answer

What is meant by lancinating?

Answer

Prolonged, chronic pain can lead to conditions in which the sensation of pain is heightened. Clinicians refer to the increased sensation of pain with time as "wind-up".

One aspect of wind-up may be the steady release of substance P in the dorsal horns. Peptides are removed slowly and can diffuse around somewhat. The continued presence of substance P might lead to cellular changes such as increased neuronal sprouting. Other cellular changes might follow from activation of NMDA receptors. Recall that these only open with prolonged depolarization, such as would occur with prolonged pain. The resulting influx of Ca++ could activate enzymes (such as nitric oxide synthase) or trigger other long lasting cellular changes. But, whatever the case, the neurons are functionally and physically changed.

Neuropathic pain can arise not only from painful stimuli acting on pain sensors but also from damaging or cutting nerves. In this category, we will discuss phantom limb pain, which occurs in amputees, and the related deafferentation pain. A neuroma, for example, might create the conditions that lead to neuropathic pain.

Sympathetically maintained pain refers, by definition, to neuropathic pain in which blocking the sympathetic nervous system helps relieve the pain. This is the case in various neuropathic pain situations. Apparently, there are interconnections between efferent sympathetic outflow and incoming afferent pain information. In addition to other types of pain medications, sympathetic ganglia may be blocked as well as circulating norepinephrine and epinephrine.

A region with this type of pain might have altered skin blood flow,edema, or abnormal sweating. With time there may be increased hair and nail growth and eventually severe degenerative changes in the muscles and bones. It can spread out from its original region. These sorts of pain syndromes need to be treated, because after a few months they can become irreversible and very refractory to treatment.

(The classification of neuropathic pain involving sympathetic effects is variable and confusing. But the term "complex regional pain syndrome" is the most common term that refers to the whole set of these types of pain syndromes.)



Quick Quiz

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Correct Answer

What class of peripheral axons include the unmyelinated axons carrying pain information?

What is the neurotransmitter released by A delta fibers?

What substance is released by C-fibers as a result of the axon reflex?

What type of ligand gated ion channel only opens following prolonged release of glutamate?

What term refers, in general, to pain due to neuronal abnormalities rather than to a painful stimulus?

Would you expect substance P to constrict or dilate blood vessels?

Does an enkephalin inhibit or excite a neuron with an axon projecting from a dorsal horn to the thalmus (in anterolateral tract)?

In what region of the brain is the periaqueductal gray?


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