Opioid control of the release of calcitonin gene-related peptide-like material from the rat spinal cord in vivo.

The possible control by opioids of the spinal release of calcitonin gene-related peptide-like material (CGRPLM) was investigated in halothane-anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid. Morphine (20 mg/kg i.v.; or at 10-100 microM added to the perfusing fluid), the mu selective agonist DAGO (10 microM) and the kappa selective agonist U 50488 H (10 microM) did not affect the spontaneous outflow of the CGRPLM. In contrast, the selective delta agonist DTLET (10 microM) significantly increased CGRPLM release. The latter effect could be prevented by the selective delta antagonist naltrindole (10 microM) as expected from the involvement of this class of opioid receptors. However, the addition of naltrindole alone to the perfusing fluid did not modify CGRPLM outflow, indicating that endogenous opioids do not exert a tonic control of CGRP-containing fibers through the stimulation of delta receptors. In contrast, intrathecal perfusion with naloxone (10 microM) or nor-binaltorphimine (10 microM), a selective antagonist of kappa receptors, produced a marked increase in spinal CGRPLM release, suggesting that endogenous opioids acting at mu and kappa receptors, respectively, exert a tonic inhibitory control of CGRP-containing fibers. Indeed, a significant decrease in the spinal release of CGRPLM release could be evoked by the combined addition of U 50488 H (10 microM) plus DAGO (10 microM) to the perfusing medium, indicating that the simultaneous stimulation of both kappa and mu receptors is required for this negative control to occur. This could notably be achieved with morphine (10 microM) in the presence of naltrindole (10 microM) which also produced a significant reduction in the spinal release of CGRPLM. In conclusion, morphine per se did not change CGRPLM release because this drug triggers opposite positive (through the stimulation of delta receptors) and negative (through the concomitant stimulation of both kappa and mu receptors) control mechanisms within the rat spinal cord.