Recent evidence suggest that endogenous
cholecystokinin (CCK) has important roles in central responses to stress.
CCK receptors are known as functional modulators of opioidergic system with a tonic antiopioid effect in nociceptive pathways. In contrast,
CCK receptor ligands are known to induce
anticonvulsant effects similar to endogenous
opioids. It is not clear whether endogenous CCK may play a role in the
anticonvulsant effects of stress, especially in those stressful paradigms that are associated with strong activation of
opioid pathways. The present study examined the role of endogenous
CCK receptors in acute stress-induced modulation of
seizure (clonic seizures induced by
pentylenetetrazole) and nociception (tail-flick) thresholds. Acute restraint stress (for 2 h) and prolonged intermittent footshock stress (30 min) both induced
opioid-dependent
anticonvulsant and antinociceptive effects. While
CCK receptor antagonist
proglumide (10, 20, or 40 mg/kg) had no effect on seizure or nociception threshold by itself, it inhibited the
anticonvulsant effects of both these types of stress while potentiating their antinociceptive effects. Moreover,
proglumide exerted a similar inhibition of the
anticonvulsant effect and potentiation of the antinociceptive effect of acute
morphine at 1 mg/kg. In contrast, brief and continuous footshock stress (3 min) that induced a nonopioid type of antinociception did not increase the seizure threshold.
Proglumide pretreatment did not alter any of these effects of brief footshock stress paradigm. The present data suggest that
CCK receptors specifically and differentially modulate the
opioid-mediated
anticonvulsant and antinociceptive effects of acute stress.