In vivo studies on spinal opiate receptor systems mediating antinociception. II. Pharmacological profiles suggesting a differential association of mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat

Abstract

The intrathecal administration of mu (morphine) and delta (D-Ala2-D-Leu5-enkephalin) but not kappa agonists (ethylketocyclazocine, bremazocine and U50488H) or partial agonists (nalbuphine and buprenorphine) produced a dose-dependent inhibition of all cutaneous thermal (hot plate and tail-flick) responses in the rat. In contrast, on visceral chemical tests (writhing), mu and kappa agonists but not delta agonists exerted a powerful suppression of the response. Whereas the ED50 of morphine on the cutaneous thermal tests did not differ from that observed on the visceral chemical test, agents with significant mu and delta activity (metkephamid and beta-endorphin) showed a prominent reduction in activity on the writhing as compared with the hot plate and tail-flick. Systemic naloxone resulted in a dose-dependent antagonism of the effect of all intrathecal agents. Estimation of the pA2 of mu agents indicated no difference on the hot plate/tail-flick and writhing (pA2 approximately 7). Kappa ligands were selectively resistant to antagonism with naloxone pA2 values for those agonists ranging from 5.9 to 6.6. These observations suggest that there are three discriminable populations of receptors in the spinal cord whose activation results in a selective modulation of the response of the animal to noxious stimuli. In addition, the selective effects of the delta agonists on cutaneous thermal and kappa agonists on visceral chemical suggest a differential coding of spinal afferents through which these stimuli are transmitted.