Differential effects of the CCK antagonist, MK-329, on analgesia induced by morphine, social conflict (opioid) and defeat experience (non-opioid) in male mice.

The effects of the potent and selective CCK antagonist, MK-329, on morphine- and environmentally-induced analgesia were examined in male mice. The results show that MK-329 (0.005-0.1 mg/kg) was devoid of intrinsic analgetic activity on the mouse tail-flick assay and, over the dose range 0.01-0.5 mg/kg, was without significant effect upon non-opioid analgesia, induced by defeat experience. However, opposite effects of MK-329 on analgesia induced by morphine and opioid-mediated social conflict analgesia were observed. That is, 0.05-0.01 mg/kg MK-329 (but not smaller doses) enhanced, and modestly prolonged, the duration of analgesia induced by 5 mg/kg morphine. In direct contrast, 0.0001-0.5 mg/kg of the CCK antagonist very potently inhibited opioid-typical analgesia in mice exposed to intense conspecific attack. In the latter studies, a residual short-lasting analgesia in mice, treated with MK-329, was found to be resistant to naloxone (5 mg/kg), indicating its non-opioid nature and confirming the lack of effect of the CCK antagonist on opioid-independent analgesia. It is suggested that the variable effects of MK-329 on morphine-induced and opioid-mediated social conflict analgesia may reflect differential, dose-dependent effects at CCK-B and CCK-A sites respectively, a proposal consistent with the 500-fold potency difference observed between the two models.