SPINAL ANTINOCICEPTION BY MORPHINE IN RATS IS ANTAGONIZED BY GALANIN RECEPTOR ANTAGONISTS

Abstract

Galanin, a 29 amino acid peptide, has been reported to possess antinociceptive properties at the spinal site and to potentiate opioid-induced antinociception. Our aim was to investigate whether also endogenous galanin interacts with an exogenously administered opioid, morphine, in the rat spinal cord. This question was investigated by use of the recently developed galanin receptor antagonists galantide [M-15, galanin-(1-13)-substance P-(5-11) amide] and M-35 [galanin-(1-13)-bradykinin-(2-9) amide]. Nociception was assessed in the rat tail-flick test using radiant heat and the rat Randall-Selitto model of inflammatory pain using vocalization as the nociceptive criterion. Intrathecal (i.t.) injections were performed in rats under ether anaesthesia. Morphine was administered either i.t. or intraperitoneally (i.p.), and the antagonists were injected i.t. [I-125]Galanin binding experiments were performed on crude synaptosomal membranes of the rat spinal cord. In the rat tail-flick test, i.t. injection of 3 mu g morphine evoked antinociception of about 75% of the maximal possible effect (% MPE). Co-injection of either 2 mu g galantide or 2 mu g M-35 with morphine almost completely abolished the antinociceptive effect of morphine. I.p. injection of 2.15 mg/kg morphine elicited about 80% MPE when given 10 min prior to i.t. saline injection. Injection of the antagonists instead of saline antagonised the antinociceptive effect of morphine partially thus showing the spinal proportion of the overall antinociceptive effect. In the rat Randall-Selitto test, 3 mu g morphine, injected i.t., produced antinociception of almost 100% MPE. Co-injection of the antagonists reduced the maximum effect partially by about 25-35%. I.p. injection of 7.5 mg/kg morphine 10 min prior to i.t. injection of saline elicited an antinociceptive effect of 90-100% MPE; injection of the antagonists instead of saline reduced the peak effect to a similar degree as after i.t. injection of 3 mu g morphine. To exclude a direct interference by morphine with the galanin receptor, in vitro binding of [I-125]galanin to a spinal synaptosomal fraction was assessed. Morphine, 10 mu M, did not interfere with the specific [I-125]galanin binding. These results provide further evidence that galanin is involved in spinal nociceptive processing. It seems to be involved in the mediation of the effects of morphine at this site, either as a co-transmitter, or subsequent to mu-receptor activation on nerve terminals or on interneurones