Cellular adaptation: Journey from smooth muscle cells to neurons

In the 1960s, it became clear that the adaptation of smooth muscle to denervation was different from that of skeletal muscle. The supersensitivity of denervated smooth muscle extended to agonists unrelated to the lost neurotransmitter and developed on a tissue-dependent time course of several days to several weeks. Several procedures, in addition to denervation, that interrupted excitatory transmission, elicited the phenomenon. The supersensitivity occurred without changes in density or affinity of receptors but correlated with a partial depolarization of the smooth muscle cells. The phenomenon could be mimicked by procedures that acutely depolarized the cells. Electrophysiological, biochemical, and molecular data established that the depolarization was due to reduced electrogenic pumping and reduced density of the Na+,K+ pump. The triggering event for the development of such supersensitivity is not interruption of contact of neurotransmitter with its receptor, but rather the decreased activity of the adapting cells. This is clear from the fact that the inhibitory action of opioids produces similar sensitivity changes in several different populations of guinea pig neurons, including S-type neurons of the myenteric plexus. Subcutaneous implantation of morphine pellets in guinea pigs induces adaptation of S neurons expressed as nonspecific subsensitivity to inhibitory agonists (opioids, alpha(2)-adrenoceptor agonists, 2-chloroadenosine) and supersensitivity to excitatory agonists (nicotine, 5-hydroxytryptamine, K+). These changes are accompanied by a partial depolarization of the S neurons and decreased electrogenic Na+,K+ pumping. Chronic implantation of morphine pellets also produces similar nonspecific changes in sensitivity in neurons of the nucleus tractus solitarius and locus ceruleus. It is suggested that depressed activity of these neurons leads to an electrophysiological adaptation, presumably due to reduced density of Na+,K+ pump proteins, as demonstrated in smooth muscle.