This week's article discusses the effects of neuropathic pain and the changes that result to the nervous systems - both peripheral and central. The original author is GARY J. BENNETT, of the Allegheny University of the Health Sciences
Introduction
The effects of neuropathic pain upon the nervous system itself - is a rather recent area of study. These changes to the nervous system result in the requirement for different treatments - for the former treatments of pain are neither applicable nor effective against this "rewired pain circuitry".
Pain-Circuit Rewiring
A further property of the drugs now under investigation is their absence of an effect on normal pain sensation. In CCI rats, dextrorphan, omega-conopeptides, gabapentin, and even felbamate caused no change in any pain index tested on the sham-operated side. Hence, the new drugs are not analgesic in the same sense as opiate drugs.
The implication is that neuropathic pain has mechanisms distinct from those of normal pain. Some of these are now beginning to emerge. For instance, sites of nerve damage may not be the sole origin of spontaneous discharge. The abnormal activity of these mechanisms may arise in dorsal root ganglia, where the damaged primary afferents have their cell bodies. Within the dorsal root ganglia, the cell bodies also exhibit an aberrant noradrenergic innervation by sympathetic fibers. Through such connections, sympathetic discharge may reach not only arterial muscle, for the normal regulation of vascular tone, but also sensory neurons. Thus, some long-recognized features of causalgia and RSD (e.g., that sympathetic-arousing stimuli such as cold or unexpected noise can cause agonizing pain) may now have a partial explanation.
Perhaps even more surprisingly, the primary afferent neurons affected by nerve damage appear to change their neurotransmitter language. Normally, pain afferents release glutamate at their synapses with dorsal-horn neurons. In addition, among neuropeptides, the pain afferents release a mixture comprised of substance P and calcitonin gene-related peptide. After nerve injury, the pain afferents continue to use glutamate but the peptide manufacture is altered. The pain afferents release a mixture of neuropeptide Y, somatostatin, vasoactive intestinal polypeptide, and galanin.
Simultaneously, substance P, which would normally be found only in small-diameter pain afferents, begins to appear in large-diameter touch fibers. Within two weeks of nerve injury, the change can be identified even in the brainstem, at the touch fibers' synaptic connections with the dorsal column nuclei (the source of the medial lemniscus). CNS circuits accustomed to one set of signals are now receiving another. One may assume that the recipient neurons must correspondingly alter their responsiveness (i.e., their receptor expression). Confirmation is not yet available, with the exception of substance-P evoked responses in the dorsal column nuclei, as demonstrated by Koichi Noguchi and colleagues at Hyogo College of Medicine, in Japan.
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