Peripheral antinociceptive effects of µ- and δ-opioid receptor agonists in NOS2 and NOS1 knockout mice during chronic inflammatory pain

The aim of this study is to investigate the involvement of nitric oxide synthesized by the inducible (NOS2) or neuronal (NOS1) nitric oxide synthases in the local antinociceptive effects produced by µ- and δ-opioid receptor agonists during chronic inflammatory pain. Peripheral inflammatory pain was induced in NOS2 and NOS1 knockout mice and their wild type littermates by the subplantar administration of complete Freund's adjuvant (30 µl). The presence of paw inflammation, mechanical allodynia and thermal hyperalgesia induced by complete Freund's adjuvant were assessed by measuring paw diameter and using the von Frey filaments and plantar tests, respectively. During chronic inflammation, NOS2 deficient mice have a more rapid recovery of paw edema and a reduced thermal hyperalgesia compared to wild type. In contrast, a reduced paw edema and mechanical allodynia, as well as a modest rapid recovery from thermal hyperalgesia were observed in NOS1 knockout mice compared to wild type. The thermal hyperalgesia induced by complete Freund's adjuvant was not completely reversed by the subplantar administration of morphine (days 4 and 7) or [d-Pen 2,5] enkephalin (DPDPE) (days 1 and 4) in NOS2 knockout mice as occurs in wild type mice. Moreover, the local administration of morphine or DPDPE also failed to reverse the decrease of ipsilateral paw withdrawal latency induced by complete Freund's adjuvant in NOS1 knockout mice throughout 10 days of peripheral inflammation. These results indicate the different roles played by nitric oxide synthesized by NOS2 or NOS1 in the maintenance of mechanical allodynia and thermal hyperalgesia induced by chronic inflammatory pain as well as, in the antinociceptive effects produced by µ- and δ-opioid receptor agonists during peripheral inflammatory pain.