Feedback inhibition of met‐enkephalin release from the rat spinal cord in vivo

The possible exitence of a feedback control by endogenous opioids of the spinal release of met‐enkephalin‐like material was assessed in vivo, in halothane‐anesthetized rats whose intrathecal space was continuously perfused with an artifical cerebrospinal fluid supplemented with various opioid‐related drugs. Both the intrathecal perfusion of the μ agonist D‐Ala 2 ‐D‐MePhe 4 ‐Gly‐ol 5 ‐enkephalin (DAGO) (10 μM) and the ∂ agonist Tyr‐D‐Thr‐Gly‐Phe‐Leu‐Thr (DTLET) (10 μM) produced a significant inhibition of the spinal outflow of met‐enkephalin‐like material. The effect of DAGO, but not that of DTLET, could be prevented by naloxone (10 μM), and, conversely, the effect of DLTET, but not that of DAGO, was no longer observed in the presence of naltrindole (10 μM). Therfore naloxone and naltrindole acted as potent and selective μ and ∂ antagonists, respectively, when perfused at 10 μM in the intrathecal space of halothane‐anesthetized rats. As expected from the lack of a tonic opioid control of spinal enkephalinergic neurones, neither naloxone nor naltrindole alone affected the spontaneous outflow of metenkephalin‐like material. However, naltrindole, but not naloxone, markedly increased the spinal overflow of met‐enkephalin‐like material due to intrathecal administration of either porcine calcitonin (10 μM) or the peptidase inhibitors thiorphan (10 μM) plus bestatin (20 μM). These data suggest that μ, but not ð, receptors are involved in a phasic opioid inhibitory control of the release of met‐enkephalin‐like material in the rat spinal cord. This control would be functional only when the concentration of extracellular endogenous opioid(s) reaches a critical level, as probably occurring in pain‐suffering subjects. ð Opioid antagonists acting selectively on the receptors involved in this feedback control might constitute a new class of analgesic drugs. © 1992 Wiley‐Liss, Inc.