Desensitization to intrathecal substance P in mice: possible involvement of opioids.

Intrathecal (i.t.) injection of substance P (SP) results in a behavioral syndrome characterized by caudally directed biting and scratching. The present results indicate that repeated injections of 10 ng of SP, administered at 60 sec intervals, result in the rapid development of tachyphylaxis to this SP-induced behavioral phenomenon. Three injections of SP produced a greatly attenuated behavioral response compared to that of a single injection of SP. Mice injected with Freund's adjuvant in the hind foot pads to produce an arthritic-like condition exhibited significantly less desensitization to SP after repeated i.t. injection compared to that in saline-injected control mice. While large doses of naloxone (5 mg/kg s.c. or 1 microgram i.t.) combined with each injection of SP completely blocked the desensitization to the effect of SP in naive mice, a smaller dose of naloxone (0.5 mg/kg administered s.c.) failed to alter the apparent tachyphylaxis to SP similar to that seen in saline-treated control mice. Pretreatment with 0.5 micrograms i.t. of beta-funaltrexamine (beta-FNA) also failed to alter the degree of apparent tachyphylaxis to SP. Co-administration of 1 microgram of fluoxetine, a serotonin reuptake inhibitor, or 1 microgram of phentolamine, an alpha-adrenergic antagonist, completely blocked the development of tachyphylaxis to i.t. SP. These results indicate that tachyphylaxis to SP appears to involve activation of the endogenous opioid system. Desensitization also appears to involve activation and inhibition of the descending adrenergic and serotonergic systems respectively.