Enhancement of the opiate withdrawal response by antipsychotic drugs in guinea-pigs is not mediated by sigma binding sites

Abstract

Haloperidol, a ‘typical’ neuroleptic, with affinity for both dopamine (DA) receptors and σ binding sites, exacerbates morphine withdrawal in guinea-pigs. In this study, the effects of σ ligands (+)- and (−)-SKF 10,047 (1 and 10 mg/kg s.c.), pentazocine (20 mg/kg s.c.) and DTG (1 and 10 mg/kg s.c.), non-competitive NMDA antagonists ketamine hydrochloride (20 mg/kg s.c.) and MK-801 (0.025, 0.1 and 1 mg/kg s.c.), ‘atypical’ neuroleptic drugs with (remoxipride 25 mg/kg s.c.) and without (raclopride 10 mg/kg s.c.; clozapine 25 mg/kg s.c.) affinity for σ sites, and atropine sulphate (20 mg/kg s.c.), were investigated on the opiate withdrawal response induced by naloxone hydrochloride (15 mg/kg s.c.) in guinea-pigs treated 2 h before with a single dose of morphine sulphate (15 mg/kg s.c.). (+)- and (−)-SKF 10,047, pentazocine, ketamine and MK-801, given 0.5 h before naloxone, significantly attenuated the increased locomotor activity and other behaviours associated with morphine withdrawal in guinea-pigs. The selective σ ligand DTG, and remoxipride had no effect on the withdrawal response but raclopride, clozapine, and atropine exacerbated the response. It is concluded that exacerbation of the morphine withdrawal response by neuroleptics is not related to σ activity but to other mechanisms. Furthermore NMDA but not σ mechanisms might play a role in the morphine withdrawal response.