Naltrindole, an opioid δ antagonist, blocks the enhancement of morphine-antinociception induced by a CCK_B antagonist in the rat

CCK has been shown to inhibit morphine antinociception, while antagonists of CCK receptors enhance morphine antinociceptive potency. These observations have led to the suggestion that CCK may function as an endogenous anti-opioid. Here, the involvement of the CCK_B receptor in modulating the antinociceptive effects of morphine has been investigated by examination of the effects of a CCK_B antagonist in the absence or presence of naltrindole, an opioid δ receptor antagonist. Intrathecal (i.th.) or subcutaneous (s.c.) L365,260 (a CCK_B antagonist) did not produce any antinociceptive actions alone in either the rat tail-flick or hot-plate tests. L365,260 pretreatment enhanced the morphine antinociceptive response after either i.th. or s.c. administration. Naltrindole did not produce any antinociceptive effect alone and did not antagonize the antinociceptive actions of morphine after either i.th. or s.c. administration. However, naltrindole blocked the enhancement of morphine antinociception produced by L365,260 when evaluated by either route. These data suggest a tonic inhibition of enkephalin release by CCK via CCK_B receptors. The subsequent enhancement of morphine antinociceptive potency may reflect the well-known modulation of morphine by enkephalins acting at opioid δ receptors.