Behavioural effect of pretreatment with opioid antagonists and sigma binding site ligands on the abnormal motor response produced by the kappa opioid agonist U50,488H in guinea pigs.

Dose-responsive motor activity induced by systemic injection of the kappa (kappa) preferring opioid agonist, U50,488H (1-10 mg/kg, s.c.) in guinea pigs was recently reported [Brent P. J. and Bot G. (1992) Psychopharmacology 107: 581-590], characterised at the higher doses used (5-10 mg/kg) by sustained postural abnormalities. The effects on the U50,488H-induced, abnormal, motor response of pharmacological manipulation of opioid receptors and sigma (sigma) sites was studied. The opioid antagonist naloxone, [5 and 15 mg/kg, subcutaneously (s.c.)], the kappa selective antagonist, norbinaltorphimine (NBNI), administered intracerebroventricularly (i.c.v., 20 and 50 nM) 0.5 hr before U50,488H, and the anticonvulsant phenytoin [25 and 50 mg/kg, intraperitoneally (i.p.)] given 1 hr before, attenuated the abnormal postures, whereas naloxone methobromide (15 mg/kg), a quaternary opioid which does not cross the blood-brain barrier, had no significant effect on the movements. In contrast, the drugs with varying affinity for sigma binding sites such as 1,3-di(2-tolyl)guanidine (DTG, 10 and 30 mg/kg), haloperidol (1 and 5 mg/kg, s.c.), dextromethorphan (1, 10 and 20 mg/kg, s.c.) and reduced haloperidol (1 mg/kg, s.c.), given 0.5-1 hr before U50,488H, exacerbated the severity of the abnormal motor activity in a dose-related manner by decreasing the latency to onset of maximum obtainable motor response and increasing the duration of the response. In addition, haloperidol (1 and 5 mg/kg, s.c.), dextromethorphan (10 mg/kg, s.c.) and DTG (30 mg/kg, s.c.), given in combination with U50,488H, induced behaviour characterised by marked oral activity. In contrast to the effect of haloperidol, pretreatment with the selective dopamine D-2 antagonist, raclopride (10 mg/kg, s.c.), had no significant effect on the abnormal movements induced by U50,488H, but did induce oral activity. These data indicate the possible involvement of kappa opioid receptors in the abnormal movement induced by U50,488H, and further demonstrate that there is an interaction between the kappa receptors and sigma sites which can influence the abnormal motor activity.