l‐Leucyl‐l‐arginine, naltrindole and d‐arginine block antinociception elicited by l‐arginine in mice with carrageenin‐induced hyperalgesia

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Abstract
1 Intraplantar injection of carrageenin into the mouse hind paw produced hyperalgesia when measured by the paw pressure test (Randall & Selitto method). 2 Subcutaneous administration of l-arginine (100–1,000 mg kg−1), a possible precursor of kyotorphin which is an endogenous analgesic neuropeptide, inhibited carrageenin-induced hyperalgesia in a dose-dependent manner. This effect was blocked by subcutaneous administration of naloxone, naltrindole, a selective δ-opioid receptor antagonist (enkephalin antagonist), and d-arginine. 3 Intracerebroventricular administration of l-leucyl-l-arginine inhibited the antinociceptive effect of systemically administered l-arginine in hyperalgesic mice. 4 Intracerebroventricular administration of l-arginine (3 and 30 μg per mouse) and kyotorphin (300 ng − 3 μg per mouse) produced antinociception in hyperalgesic mice. The antinociceptive effects of l-arginine but not kyotorphin were blocked by intracerebroventricular administration of d-arginine. 5 These results suggest that l-arginine-induced antinociception is mediated by activation of ‘kyotorphinergic’ nerves followed by activation of the ‘opioidergic’ (possible ‘enkephalinergic’) nerves in the central nervous system.