RT Journal Article
SR Electronic
T1 The heroin metabolite, 6-monoacetylmorphine, activates delta opioid receptors to produce antinociception in Swiss-Webster mice.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1222
OP 1231
VO 268
IS 3
A1 J J Rady
A1 F Aksu
A1 J M Fujimoto
YR 1994
UL http://jpet.aspetjournals.org/content/268/3/1222.abstract
AB Heroin activates delta receptors, whereas morphine activates mu receptors, in the brain of Swiss-Webster mice, to produce antinociception. The present study determined the type of opioid receptor activated by 6-monoacetylmorphine (MAM), a metabolite of heroin. Intracerebroventricular MAM-induced inhibition of the tail-flick response was reduced by coadministration of naltrindole (a delta opioid receptor antagonist), suggesting that i.c.v. MAM, like i.c.v. heroin, acted on delta receptors. This delta receptor-mediated response was not affected by intrathecal (i.t.) administration of yohimbine and methysergide. Thus, the descending noradrenergic and serotonergic neuronal pathways, which are activated by i.c.v. morphine, were not involved in MAM antinociception. In the spinal cord, coadministration of naltrindole with MAM, i.t., decreased antinociception suggesting that MAM acted on spinal delta receptors. This finding is in contrast to i.t. heroin which acts on mu receptors in the spinal cord. These receptor selectivities were also demonstrated for systemically administered MAM and heroin. Thus, i.c.v. naltrindole inhibited both MAM- and heroin-induced antinociception, but i.t. naltrindole only inhibited the MAM response. The following results in ICR mice contrast with those above. Antinociception induced by i.c.v. MAM was decreased by coadministration of naloxone, but not naltrindole, suggesting that MAM, like morphine and heroin, acted on supraspinal mu receptors. Also, this MAM response was inhibited by i.t. administration of methysergide which is consistent with supraspinal mu receptor activation. Furthermore, i.t. MAM acted on spinal mu receptors because i.t. administration of naloxone, but not naltrindole, produced inhibition. In conclusion, the ability to ascribe delta receptor selectivity to the action of heroin and MAM in Swiss-Webster mice served to reinforce the concept that heroin and MAM act primarily on their own and not through formation of morphine. Further elucidation of the difference in heroin and MAM receptor selectivities between Swiss-Webster and ICR mice might contribute to a better understanding of opioid receptor mechanisms.