Spinal dynorphin A (1–17): Possible mediator of antianalgesic action

Earlier studies from this laboratory indicated that intracerebroventricular administration of physostigmine and clonidine activated both a spinal descending analgesic and antianalgesic system. It was proposed that the latter was mediated spinally by dynorphin A (1–17), because small intrathecal doses (fmol) of dynorphin A (1–17) antagonized analgesia, while intrathecal administration of naloxone and nor-binaltorphimine (at doses which had no effect on spinal mu and kappa receptors) enhanced analgesia by attenuating the antianalgesic component. In the present studies in mice, using the tail-flick response, intrathecal administration of dynorphin antibody (antiserum to dynorphin) enhanced the analgesic effect of (10 min) physostigmine and clonidine given intraventricularly. Peak effect for the antiserum was at 1 hr. Inhibition of the tail-flick response, induced by DAMGO (Tyr- d-Ala 2-Gly-NMePhe 4-Gly-ol 5, a mu agonist), U50, 488 H { trans-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate hydrate, a kappa agonist} and morphine was also enhanced by intrathecal administration of dynorphin antiserum. Thus, a variety of analgesic agonists appear to activate a dynorphinmediated antianalgesic system. Such a system appears not to be activated by intraventricular administration of β-endorphin and DPDPE ( d-Pen 2- d-Pen 5-enkephalin, a delta agonist) because neither β-endorphin- nor DPDPE-induced analgesia was enhanced by intrathecal administration of antiserum. The results of the experiments with the antibody provide further evidence to support the role of dynorphin A (1–17), as a putative endogenous opioid, which mediates an antianalgesic descending system in the spinal cord.