δ-Opioid receptor antagonists attenuate motor activity induced by amphetamine but not cocaine

Naloxone and naltrindole attenuate the locomotor response to amphetamine, implicating δ-opioid receptors in the opioid-antagonist/amphetamine interaction. To determine the role of δ-opioid receptor subtypes in this phenomenon, rats were pretreated with the following selective antagonists administered intracisternally: naltrindole, [D-Ala², Leu⁵, Cys⁶]enkephalin (DALCE, δ₁ receptor selective), naltrindole-5′-isothiocyanate (δ₂ receptor selective). Cumulative dose-response curves to amphetamine were constructed (saline, 0.1, 0.4, 1.6 and 6.4 mg/kg s.c.), with injections every 30 min. Naltrindole was also tested against cumulative doses of cocaine (saline, 3.0, 10, 30 and 56 mg/kg i.p.). Gross and fine motor activity were recorded for 20 min, commencing 10 min postinjection. Amphetamine and cocaine dose dependently increased both gross and fine movements. Naltrindole (10 μg) attenuated the gross but not fine activity response to amphetamine, but 10 or 30 μg failed to influence the response to cocaine. Naltrindole-5′-isothiocyanate (30 μg) attenuated slighty but significantly the gross activity response to amphetamine, whereas DALCE (30 μg) was without effect. However, a combination of 10 μg each of DALCE and naltrindole-5′-isothiocyanate markedly attenuated the amphetamine-induced increases in gross movements without altering fine activity. These data provide further evidence for the involvement of δ-opioid receptors in the modulation of behavioral effects of amphetamine; both δ₁- and δ₂-opioid receptors appear to play a role. The differential effects of opioid antagonists on locomotor activity stimulated by amphetamine and cocaine suggests differences in the mechanism of action of these drugs not previously appreciated.