BEHAVIORAL-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 ka ppa (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) Psych opharmacology 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 manipulatio n of opioid receptors and sigma (sigma) sites was studied. The opioid antagonist naloxone, 5 and 15 mg/kg, subcutaneously (s.c.)!, the kapp a selective antagonist, norbinaltorphimine (NBNI), administered intrac erebroventricularly (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 nalo xone 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 a 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 reduc ed haloperidol (1 mg/kg, s.c.), given 0.5-1 hr before U50,488H, exacer bated the severity of the abnormal motor activity in a dose-related ma nner by decreasing the latency to onset of maximum obtainable motor re sponse and increasing the duration of the response. In addition, halop eridol (1 and 5 mg/kg, s.c.), dextromethorphan (10 mg/kg, s.c.) and DT G (30 mg/kg, s.c.), given in combination with U50,488H, induced behavi our characterised by marked oral activity. In contrast to the effect o f haloperidol, pretreatment with the selective dopamine D-2 antagonist , raclopride (10 mg/kg, s.c.), had no significant effect on the abnorm al movements induced by U50,488H, but did induce oral activity. These data indicate the possible involvement Of kappa opioid receptors in th e abnormal movement induced by U50,488H, and further demonstrate that there is an interaction between the kappa receptors and sigma sites wh ich can influence the abnormal motor activity.