PHYSIOLOGIC ASPECTS OF PAIN

The stimuli that activate pain receptors vary from one tissue to another. As pointed out above, the adequate stimulus for skin is one that has the potential to injure tissue, i.e., pricking, cutting, crushing, burning, and freezing. These stimuli are ineffective when applied to the stomach and intestine, where pain is produced by an engorged or inflamed mucosa, distention or spasm of smooth muscle, and traction on the mesenteric attachment. In skeletal muscle, pain is caused by ischemia (the basis of intermittent claudication), necrosis, hemorrhage, and injection of irritating solutions, as well as by injuries of connective tissue sheaths. Prolonged contraction of skeletal muscle evokes an aching type of pain. Ischemia is also the most important cause of pain in cardiac muscle. Joints are insensitive to pricking, cutting, and cautery, but pain can be produced in the synovial membrane by inflammation and by exposure to hypertonic saline. The stretching and tearing of ligaments around a joint can evoke severe pain. Injuries to the periosteum give rise to pain but probably not to other sensations. Arteries are a source of pain when pierced by a needle or involved in an inflammatory process. Distention of arteries, as occurs with thrombotic or embolic occlusion, and excessive arterial pulsation, as in migraine, may be sources of pain; other mechanisms of headache relate to traction on arteries and the meningeal structures by which they are supported (see Chap. 10). Pain due to intraneural lesions probably arises from the sheaths of the nerves. Nerve root(s) and sensory ganglia, when compressed (e.g., by a ruptured disc), give rise to pain.
With damage to tissue, there is a release of proteolytic enzymes, which act locally on tissue proteins to liberate substances that excite peripheral nociceptors. These pain-producing substances—which include histamine, prostaglandins, serotonin, and similar polypeptides as well as potassium ions—elicit pain when they are injected intra-arterially or applied to the base of a blister. Other pain-producing substances such as kinins are released from sensory nerve endings or are carried there by the circulation. Also, vascular permeability may be increased by these substances.
In addition, direct stimulation of nociceptors releases polypeptide mediators that enhance pain perception. The best-studied of these is substance P, which is released from the nerve endings of C fibers in the skin during peripheral nerve stimulation. It causes erythema by dilating cutaneous vessels and edema by releasing histamine from mast cells; it also acts as a chemoattractant for leukocytes. This reaction, called neurogenic inflammation by White and Helme, is mediated by antidromic action potentials from the small nerve cells in the spinal ganglia and is the basis of the axon reflex of Lewis. This reaction is abolished in certain peripheral nerve diseases and can be studied electrophysiologically as an aid to clinical localization.
Perception of Pain
The threshold for perception of pain, i.e., the lowest intensity of a stimulus recognized as pain, is approximately the same in all persons. It is lowered by inflammation, a process that is called sensitization and is clinically important because in sensitized tissues ordinarily innocuous stimuli can produce pain. The pain threshold is, of course, raised by local anesthetics and by certain lesions of the nervous system as well as by centrally acting analgesic drugs. Mechanisms other than lowering or raising the pain threshold are important as well. Placebos reduce pain in about one-third of the groups of patients in which such effects have been recorded. Acupuncture at sites anatomically remote from painful operative fields apparently reduces the pain in some individuals. Distraction and suggestion, by turning attention away from the painful part, reduce the awareness of and response to pain. Strong emotion (fear or rage) suppresses pain, presumably by activation of the above-described descending adrenergic system. The experience of pain appears to be lessened in manic states and enhanced in depression. Neurotic patients in general have the same pain threshold as normal subjects, but their reaction may be excessive or abnormal. The pain thresholds of frontal lobotomized subjects are also unchanged, but they react to painful stimuli only briefly or casually if at all. The degrees of emotional reaction and verbalization (complaint) also vary with the personality and character of the patient.
The conscious awareness or perception of pain occurs only when pain impulses reach the thalamocortical level. The precise roles of the thalamus and cortical sensory areas in this mental process are not fully understood, however. For many years it was taught that the recognition of a noxious stimulus as such is a function of the thalamus and that the parietal cortex is necessary for appreciation of the intensity, localization, and other discriminatory aspects of sensation. This traditional separation of sensation (in this instance awareness of pain) and perception (awareness of the nature of the painful stimulus) has been abandoned in favor of the view that sensation, perception, and the various conscious and unconscious responses to a pain stimulus comprise an indivisible process. That the cerebral cortex governs the patient's reaction to pain cannot be doubted, however. It is also likely that the cortex can suppress or otherwise modify the perception of pain in the same way that corticofugal projections from the sensory cortex modify the rostral transmission of other sensory impulses from thalamic and dorsal column nuclei. It has been shown that central transmission in the spinothalamic tract can be inhibited by stimulation of the sensorimotor areas of the cerebral cortex, and, as indicated above, a number of descending fiber systems have been traced to the dorsal horn laminae from which this tract originates.
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 with the pharmacologic 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. These connections are illustrated in Fig. 8-5.
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-d and C fibers. Furthermore, these effects can be reversed by the narcotic antagonist naloxone. Interestingly, naloxone can reduce some forms of stimulation-produced 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 pain-relieving 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.
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 (Hughes et al). These endogenous, morphine-like compounds are generically referred to as endorphins, meaning “the morphines within.” The most widely studied of these compounds are b-endorphin, a peptide sequence of the pituitary hormone b-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, opiate receptors are essentially enkephalin receptors. 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. 8-6. A subgroup of dorsal horn interneurons also contain enkephalin; they are in contact with spinothalamic tract neurons.




Figure 8-6 Theoretical mechanism of action of enkephalin (endorphin) and morphine on the transmission of pain impulses from the periphery to the CNS. Spinal interneurons containing enkephalin synapse with the terminals of pain fibers and inhibit the release of the presumptive transmitter, substance P. As a re-sult, the receptor neuron in the dorsal horn receives less excita-tory (pain) impulses and transmits fewer pain impulses to the brain. Morphine binds to unoccupied enkephalin receptors, mimicking the pain-suppressing effects of the endogenous opiate enkephalin.


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. Opiate addiction might conceivably be accounted for in this way, and also the discomfort that follows withdrawal of the drug. Indeed, it is known that some of these peptides not only relieve pain but suppress withdrawal symptoms. It has been speculated that in the limbic regions, disturbances in the formation of neurotransmitters could be the basis of unpleasant and distressing emotional states (e.g., depression).
Finally it should be noted that the descending pain-control systems probably contain noradrenergic and serotoninergic 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 serotoninergic neurons. Descending fibers from the latter site inhibit dorsal horn cells concerned with pain transmission, perhaps providing a rationale for the use of certain serotonin agonists in patients with chronic pain.