1 Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressantinduced antinociception. 2 All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also e ective antinociceptive agents in this nociceptive assay. 3 Opioid antagonists, naloxone (0.5 mg kg 71 , s.c.) and naltrindole (1 mg kg 71 , s.c.), shifted the doseresponse relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no e ect upon morphine antinociception. Aspirin antinociception remained una ected by both opioid antagonists. 4 The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg 71 (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5 When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant-or morphine-induced antinociception. However, acetorphan had no e ect on aspirin antinociception. 6 Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is di erent from that of the non-steroidal anti-in¯ammatory drugs. 7 These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without a ecting morphine antinociception, implicates the d-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.

Abstract:The effects of a -opioid receptor agonist on acute amphetamine-induced behavioral activation and dialysate levels of dopamine and glutamate in the ventral striatum were investigated. Amphetamine (2.5 mg/kg i.p.) evoked a substantial increase in rearing, sniffing, and hole-poking behavior as well as dopamine and glutamate levels in the ventral striatum of awake rats. U-69593 (0.32 mg/kg s.c.) significantly decreased the amphetamineevoked increase in behavior and dopamine and glutamate levels in the ventral striatum. Reverse dialysis of the selective -opioid receptor antagonist, nor-binaltorphimine, into the ventral striatum antagonized the effects of U-69593 on amphetamine-induced behavior and dopamine and glutamate levels. Reverse dialysis of low calcium (0.1 mM) into the ventral striatum decreased basal dopamine, but not glutamate, dialysate levels by 91% 45 min after initiation of perfusion. Strikingly, 0.1 mM calcium perfusion significantly reduced the 2.5 mg/kg amphetamine-evoked increase in dopamine and glutamate levels in the ventral striatum, distinguishing a calciumdependent and a calcium-independent component of release. U-69593 did not alter the calcium-independent component of amphetamine-evoked dopamine and glutamate levels. These data are consistent with the view that a transsynaptic mechanism augments the increase in dopamine and glutamate levels in the ventral striatum evoked by a moderately high dose of amphetamine and that stimulation of -opioid receptors suppresses the calcium-dependent component of amphetamine's effects.

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