Causalgia, pathological pain, and adrenergic receptors

Control of expression of molecular receptors for chemical messengers and modulation of these receptors’ activity are now established as ways to alter cellular reaction. This paper extends these mechanisms to the arena of pathological pain by presenting the hypothesis that increased expression of α-adrenergic receptors in primary afferent neurons is part of the etiology of pain in classical causalgia. It is argued that partial denervation by lesion of peripheral nerve or by tissue destruction induces a change in peripheral nociceptors, making them excitable by sympathetic activity and adrenergic substances. This excitation is mediated by α-adrenergic receptors and has a time course reminiscent of experimental denervation supersensitivity. The change in neuronal phenotype is demonstrable after lesions of mixed nerves or of the sympathetic postganglionic supply. Similar partial denervations also produce a substantial increase in the number of dorsal root ganglion neurons evidencing the presence of α-adrenergic receptors. The hypothesis proposes the increased presence of α-adrenergic receptors in primary afferent neurons to result from an altered gene expression triggered by cytokines/growth factors produced by disconnection of peripheral nerve fibers from their cell bodies. These additional adrenergic receptors are suggested to make nociceptors and other primary afferent neurons excitable by local or circulating norepinephrine and epinephrine. For central pathways, the adrenergic excitation would be equivalent to that produced by noxious events and would consequently evoke pain. In support, evidence is cited for a form of denervation supersensitivity in causalgia and for increased expression of human α-adrenergic receptors after loss of sympathetic activity.

Src, a molecular switch governing gain control of synaptic transmission mediated by N-methyl-d-aspartate receptors

The N-methyl-d-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activity of NMDA receptors is regulated by the protein tyrosine kinase, Src. Recently it has been discovered that, by means of up-regulating NMDA receptor function, activation of Src mediates the induction of the lasting enhancement of excitatory transmission known as long-term potentiation in the CA1 region of the hippocampus. Also, Src has been found to amplify the up-regulation of NMDA receptor function that is produced by raising the intracellular concentration of sodium. Sodium concentration increases in neuronal dendrites during high levels of firing activity, which is precisely when Src becomes activated. Therefore, we propose that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.

The area code hypothesis revisited: Olfactory receptors and other related transmembrane receptors may function as the last digits in a cell surface code for assembling embryos

Recent evidence emerging from several laboratories, integrated with new data obtained by searching the genome databases, suggests that the area code hypothesis provides a good heuristic model for explaining the remarkable specificity of cell migration and tissue assembly that occurs throughout embryogenesis. The area code hypothesis proposes that cells assemble organisms, including their brains and nervous systems, with the aid of a molecular-addressing code that functions much like the country, area, regional, and local portions of the telephone dialing system. The complexity of the information required to code cells for the construction of entire organisms is so enormous that we assume that the code must make combinatorial use of members of large multigene families. Such a system would reuse the same receptors as molecular digits in various regions of the embryo, thus greatly reducing the total number of genes required. We present the hypothesis that members of the very large families of olfactory receptors and vomeronasal receptors fulfill the criteria proposed for area code molecules and could serve as the last digits in such a code. We discuss our evidence indicating that receptors of these families are expressed in many parts of developing embryos and suggest that they play a key functional role in cell recognition and targeting not only in the olfactory system but also throughout the brain and numerous other organs as they are assembled.