The role of opioid receptor subtypes in the development of behavioral sensitization to ethanol

Nonspecific blockade of opioid receptors has been found to prevent development of behavioral sensitization to ethanol. Whether this effect is achieved through a specific opioid receptor subtype, however, is not clear. The present study investigated, for the first time, the role of specific opioid receptor subtypes in the development of ethanol-(2.5 g/kg/day; six sessions) induced locomotor sensitization in mice. We confirmed previous results showing that the nonspecific antagonism of opioid receptors (naltrexone; 0-2 mg/kg) prevented the development of behavioral sensitization to ethanol, an effect attained at doses presumed to occupy only mu opioid receptors. This was confirmed by using the selective mu opioid receptor antagonist CTOP (0-1.5 mg/kg), which also blocked sensitization to ethanol. The selective delta receptor antagonist, naltrindole (0-10 mg/kg), however, did not alter sensitization. We further assessed the role of mu opioid receptors in sensitization to ethanol by exploring the involvement of mu(1), mu(1+2), and mu(3) opioid receptor subtypes. Results of these experiments revealed that the blockade of mu(1) (naloxonazine; 0-30 mg/kg) or mu(3) opioid receptors (3-methoxynaltrexone; 0-6 mg/kg) did not prevent locomotor sensitization to ethanol. Using naloxonazine under treatment conditions that block mu(1+2) opioid receptor subtypes we observed a retarded sensitization. The present data suggest that the concurrent inactivation of all mu opioid receptor subtypes may be required to prevent the neural adaptations underlying the development of behavioral sensitization to ethanol. In addition, these results support previous data suggesting a putative role for the mu opioid receptor endogenous ligand, beta-endorphin, and the hypothalamic arcuate nucleus in ethanol sensitization.