Opioid receptor agonists selective for mu and kappa receptors attenuate methamphetamine-induced behavioral sensitization in the mouse.

Abstract

The effects of intracerebroventricular (i.c.v.) injection of the mu-selective opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) and the kappa-selective opioid receptor agonist dynorphin A-(1-13) on the development of methamphetamine-induced behavioral sensitization in the mouse were determined using multidimensional behavioral analyses based upon a capacitance system. Methamphetamine (2 mg/kg, s.c.) was administered to mice on 6 occasions at 3- or 4-d intervals. The methamphetamine-induced increase in linear locomotion and circling was markedly augmented by repeated administrations (3 or more times) of the drug, showing behavioral sensitization. Although repeated administrations of DAMGO (0.003 and 0.01 microgram, i.c.v.) or dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) alone did not produce any significant effects on behavior, repeated administrations of DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) attenuated the behavioral sensitization induced by methamphetamine (2 mg/kg, s.c.). The attenuating effects of DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) were fully reversed by withdrawal of these drugs for 3 weeks. Additionally, a single administration of DAMGO (0.003 and 0.01 microgram, i.c.v.) or dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) alone did not produce any significant effects on behavior; DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) only attenuated the behavioral sensitization which had previously been developed by methamphetamine (2 mg/kg,s.c.). These results suggest that opioid receptor agonists selective for mu and kappa receptors play an inhibitory role in the development of methamphetamine-induced behavioral sensitization.