Endogenous Pain-Control Mechanisms

In recent years, the most important contribution to our understanding of pain has been the discovery of a neuronal
analgesia system which can be activated by the administration of opiates or by naturally occurring brain substances
that share the properties of opiates. This endogenous system was first demonstrated by Reynolds, who found that
stimulation of the ventrolateral periaqueductal gray matter in the rat produced a profound analgesia without altering
behavior or motor activity. Subsequently, stimulation of other discrete sites in the medial and caudal regions of the
diencephalon and rostral bulbar nuclei (notably raphe magnus and paragigantocellularis) were shown to have the same
effect. Under the influence of such electrical stimulation, the animal could be operated upon without anesthesia and
move around in an undisturbed manner despite the administration of noxious stimuli. Investigation disclosed that the
effect of stimulation-produced analgesia (SPA) is to inhibit the neurons of laminae I, II, and V of the dorsal horn, i.e.,
the neurons that are activated by noxious stimuli. In human subjects, stimulation of the midbrain periaqueductal gray
matter through stereotactically implanted electrodes has also produced a state of analgesia, though not consistently.
Other sites in which electrical stimulation is effective in suppressing nociceptive responses are the rostroventral
medulla (nucleus raphe magnus and adjacent reticular formation) and the dorsolateral pontine tegmentum. These
effects are relayed to the dorsal horn gray matter via a pathway in the dorsolateral funiculus of the spinal cord.
Ascending pathways from the dorsal horn, conveying noxious somatic impulses, are also important in activating the
modulatory network.
As indicated earlier, opiates also act pre- and postsynaptically on the neurons of laminae I and V of the dorsal horn,
suppressing afferent pain impulses from both the A-_ and C fibers. Furthermore, these effects can be reversed by the
narcotic antagonist naloxone. Interestingly, naloxone can reduce some forms of stimulationproduced analgesia.
Levine and colleagues have demonstrated that not only does naloxone enhance clinical pain but it also interferes with
the pain relief produced by placebos. These observations suggest that the heretofore mysterious beneficial effects of
placebos (and perhaps of acupuncture) may be due to activation of an endogenous system that shuts off pain through
the release of painrelieving endogenous opioids, or endorphins (see below). Prolonged pain and fear are the most
powerful activators of this endogenous opioid-mediated modulating system. The same system is probably operative
under a variety of other stressful conditions; for example, some soldiers, wounded in battle, require little or no
analgesic medication (“stress-induced analgesia”). The opiates also act at several loci in the brainstem, at sites
corresponding with those producing analgesia when stimulated electrically and generally conforming to areas in
which neurons with endorphin receptors are localized.
Dysesthesia: Any abnormal sensation described as unpleasant by the patient Hyperalgesia: Exaggerated pain response
from a normally painful stimulus; usually includes aspects of summation with repeated stimulus of constant intensity
and aftersensation Hyperpathia: Abnormally painful and exaggerated reaction to a painful stimulus; related to
hyperalgesia Hyperesthesia (hypesthesia): Exaggerated perception of touch stimulus Allodynia: Abnormal perception
of pain from a normally nonpainful mechanical or thermal stimulus; usually has elements of delay in perception and
of aftersensation Hypoalgesia (hypalgesia): Decreased sensitivity and raised threshold to painful stimuli Anesthesia:
Reduced perception of all sensation, mainly touch Analgesia: Reduced perception of pain stimulus Paresthesia:
Mainly spontaneous abnormal sensation that is not unpleasant; usually described as “pins and needles” Causalgia:
Buring pain in the distribution of one or more peripheral nerves Soon after the discovery of specific opiate receptors in
the central nervous system (CNS), several naturally occurring peptides, which proved to have a potent analgesic effect
and to bind specifically to opiate receptors, were identified (see Hughes et al for a summary of these substances).
These endogenous, morphine-like compounds are generically referred to as endorphins, meaning “the morphines
within.” The most widely studied are _-endorphin, a peptide sequence of the pituitary hormone _-lipotropin, and two
other peptides, enkephalin and dynorphin. They are found in greatest concentration in relation to opiate receptors in
the midbrain. At the level of the spinal cord, exclusively enkephalin receptors are found. A theoretical construct of the
roles of enkephalin (and substance P) at the point of entry of pain fibers into the spinal cord is illustrated in Fig. 8-4. A
subgroup of dorsal horn interneurons also contains enkephalin; they are in contact with spinothalamic tract neurons.
Thus it would appear that the central effects of a painful condition are determined by many ascending and descending
systems utilizing a variety of transmitters. A deficiency in a particular region would explain persistent or excessive
pain. Some aspects of opiate addiction and also the discomfort that follows withdrawal of the drug might conceivably
be accounted for in this way. Indeed, it is known that some of these peptides not only relieve pain but suppress
withdrawal symptoms.
Finally it should be noted that the descending pain-control systems contain noradrenergic and serotonergic as well as
opiate links. A descending norepinephrine-containing pathway, as mentioned, has been traced from the dorsolateral
pons to the spinal cord, and its activation blocks spinal nociceptive neurons. The rostroventral medulla contains a
large number of serotonergic neurons. Descending fibers from the latter site inhibit dorsal horn cells concerned with
pain transmission, perhaps providing a rationale for the use of certain antidepression medications that are serotonin
agonists in patients with chronic pain.