Analgesic effects of morphine and loperamide in the rat formalin test: Interactions with NMDA receptor antagonists

To reveal peripheral components of opiate analgesia, effects of loperamide, opioid agonist which does not penetrate the blood-brain barrier, were examined in formalin and acute thermal pain tests in comparison with morphine. Formalin administration induces pain behaviour such licking/biting of injected paw expressed as two phases. The first phase is caused by C-fibre activation due to peripheral stimulation, the second phase attributed to ongoing input from peripheral site, leading to spinal hyperexcitability, which is dependent on N-methyl-d-aspartate (NMDA) receptor activation. Loperamide (3-10 mg/kg) and morphine (6 mg/kg) reduced formalin-induced nociceptive behaviours and these effects were reversed by naloxone methiodide (0.03-10 mg/kg), opioid receptor antagonist which poorly penetrates the blood-brain barrier. Loperamide action was enhanced only by centrally active NMDA receptor antagonists memantine (3 mg/kg) and CGP 37849 (3 mg/kg), but not by NMDA/glycineB receptor antagonists showing weak or no central nervous system (CNS) activity. Present results suggest that central NMDA receptor blockade may be necessary to enhance analgesia induced through peripheral opioid mechanisms in formalin-evoked nociception.