Subcutaneous injection of diluted formalin (0.25 microliter of 0.5%) caused a biphasic pain response in mice. The first phase of pain was observed during the first 5 min., while the second phase occurred 10-30 min. after formalin administration. With the formalin test, it was found that the antinociception produced by the GABA-A antagonist, picrotoxin, and the GABA-B antagonist, phaclofen, was abolished when employed in combination. The opioid antagonist naloxone and antimuscarinic atropine also decreased the picrotoxin response. However, sulpiride, SCH 23390, phenoxybenzamine and propranolol did not alter the picrotoxin response. Administration of naloxone, sulpiride and propranolol showed a pain response. The data indicate that dopaminergic and adrenergic mechanisms may not be involved in the picrotoxin antinociceptive effect. However, postsynaptic GABA-A and GABA-B may be involved in the drug effect, and involvement of opioid or cholinergic systems can not be excluded.

In the present study, the effect of cholecystokinin agonists and antagonists on dependence to morphine in mice has been investigated. Mice were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily for 2-4 days, and a last dose of morphine (50 mg/kg) was administered on day 3, 4 or 5. Withdrawal syndrome (jumping) was precipitated by naloxone (2.5, 5 and 10 mg/kg) which was administered intraperitoneally 2 hr after the last dose of morphine. To study the effects of cholecystokinin receptor agonists or antagonists, 10 injection of morphine (3 administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. Cholecystokinin-8 (0.001-0.01 mg/kg), low doses of the cholecystokinin agonists caerulein (0.00001 and 0.0001 mg/kg) and, unsulfated cholecystokinin (but not high doses) as well as the antagonists MK-329 (0.5-1 mg/kg) and L-365,260 (0.5-1 mg/kg) elicit reduction of the nalaxone-induced jumping. The inhibition of jumping induced by caerulein was reduced with the selective cholecystokinin antagonists MK-329 and L-365,260. It is concluded that cholecystokinin mechanism(s) may be involved in morphine dependence, that the agonists may act on a presynaptic receptors and that the antagonists may work on postsynaptic receptors.