Inhibition of adenylate cyclase and induction of heterologous desensitization by kappa agonists in rat spinal cord.

Using crude P2 membranes of adult rat spinal cord we were able to show that the K opiate agonist U50488 significantly and dose-dependently inhibited the basal cyclase activity, while mu (DAGO) and delta (DADL) agonists were ineffective. The regulatory action was stereospecific and required the presence of GTP plus Na+ as well as Ca2+ ions. This inhibitory effect of K agonists was also observed when the cyclase activity was stimulated by forskolin. Similar inhibition was observed in spinal cord-dorsal root ganglion cocultures. Following chronic exposure of cultured cells to etorphine or U50488, the K agonists lost their ability to inhibit the cyclase. Furthermore, the desensitization process appeared to be heterologous, since the alpha 2 adrenergic agonist, norepinephrine and the muscarinic agonist, carbachol exhibited significant lower potency for inhibiting cyclase activity when compared to control cultures. These data suggest that in spinal cord, opiate receptors of the K type are negatively coupled to adenylate cyclase and the induction of tolerance produced by K agonists is related to alterations of post-receptor regulatory components.