Development of morphine tolerance and physical dependence in rats depleted of brain catecholamines by 6-hydroxydopamine

Abstract

The present study was undertaken to evaluate the roles of brain norepinephrine (NE) and/or dopamine (DA) in the development of morphine tolerance and physical dependence in rats. Rats were permanently depleted of brain catecholamines (CA, i.e. NE + DA) or DA by 6-hydroxydopamine (6-OHDA) treatment alone or desmethylimipramine plus 6-OHDA treatment at two weeks of age. Five weeks after either treatment, twice daily morphine injections were begun and continued for 32 consecutive days. The antinociceptive activity of morphine in the tail-flick test and the naloxone-precipitated abstinence syndrome were periodically observed throughout the course of chronic morphine treatment. A decreased antinociceptive response to morphine occurred in DA-depleted rats in both the non-tolerant and tolerant states, but the development of tolerance was not affected. The antinociceptive effect of morphine was not modified in either non-tolerant or tolerant CA (NE + DA)-depleted rats, nor was the development of tolerance affected. The spontaneous withdrawal syndrome after abrupt cessation of morphine after 32 days of treatment was markedly enhanced in CA-depleted rats. The results suggest that DA may be involved in mediating the antinociceptive effect of morphine, but not in the development of tolerance to that effect.