KAPPA-RECEPTOR/MU-RECEPTOR INTERACTIONS IN THE OPIOID CONTROL OF THE INVIVO RELEASE OF SUBSTANCE P-LIKE MATERIAL FROM THE RAT SPINAL-CORD

The possible involvement of mu and kappa receptors in the opioid control of the spinal release of substance P-like material was assessed in vivo, in halothane-anaesthetized rats whose intrathecal space was continuously perfused with an artificial cerebrospinal fluid supplemented with various opioid receptor agonists and antagonists. Whereas the intrathecal perfusion with the mu agonist DAGO (10 muM) significantly enhanced (approximately + 50%) the spontaneous release of substance P-like material, that with the kappa agonist U 50488 H (10 muM) produced no change in the peptide outflow. The respective antagonists naloxone (10 muM) for the mu receptors and nor-binaltorphimine (10 muM) for the kappa receptors did not affect the spontaneous release of substance P-like material, indicating that endogenous opioids acting at mu and kappa receptors do not exert a tonic control on substance P-containing neurons in the spinal cord of halothane-anaesthetized rats. However, as expected from the involvement of mu receptors, the stimulatory effect of DAGO on the peptide outflow could be prevented by naloxone but not nor-binaltorphimine. Furthermore, instead of an increase with DAGO alone, a significant decrease in the spinal release of substance P-like material was observed upon the intrathecal perfusion with DAGO plus U 50488 H. Additional experiments with the respective mu and kappa antagonists naloxone and nor-binaltorphimine demonstrated that this effect actually resulted from the simultaneous stimulation of mu and kappa receptors. As previous studies showed that delta agonists also reduce the release of substance P from primary afferent fibres, the present data could explain why non-selective opioid agonists such as morphine acting at delta, mu and kappa receptors are especially potent to reduce the peptide release through additive inhibitory influences mediated by the stimulation of delta receptors on the one hand and that of mu plus kappa receptors on the other hand. Such additive inhibitory influences on substance P-containing fibres probably contribute to the potent analgesic action of non-specific opioids administered via the intrathecal route.