Modulation of Histamine Release in the Rat Brain by K ‐Opioid Receptors

Abstract

The opioid modulation of histamine release was studied in rat brain slices labeled with L-[3H]histidine. The K+-induced [3H]histamine release from cortical slices was progressively inhibited by the preferential .kappa.-agonists ketocyclazocine, dynorphin A (1-13), Cambridge 20, spiradoline, U50,488H, and U69,593 in increasing concentrations. In contrast, the .mu.-agonists morphine, morphiceptin, and Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol(DAGO) were ineffective as were the preferential .delta.-agonists [D-Ala2,D-Leu5]enkephalin (DA-DLE) and [D-Pen2,D-Pen5]enkephalin (DPDPE). Nor-binaltorphimine (nor-BNI) and MR 2266, two preferential .kappa.-antagonists, reversed the inhibitory effect of the various .kappa.-agonists more potently than did not naloxone, with mean Ki values of 4 nM and 25 nM, respectively. The effects of ketocyclazocine and naloxone also were seen in slices of rat striatum, another brain region known to contain histaminergic nerve endings. We conclude that .kappa.-opioid receptors, presumably located on histaminergic axons, control histamine release in the brain. However, nor-BNI and naloxone failed, when added alone, to enhance significantly [3H]histamine release from cerebral cortex or striatum, and bestatin, an aminopeptidase inhibitor, failed to decrease K+-evoked [3H]histamine release. These two findings suggest that under basal conditions these .kappa.-opioid receptors are not tonically activated by endogenous dynorphin peptides. The inhibition of cerebral histamine release by .kappa.-agonists may mediate the sedative actions of these agents in vivo.