Effects of treatment with a carbon monoxide-releasing molecule and a heme oxygenase 1 inducer in the antinociceptive effects of morphine in different models of acute and chronic pain in mice.

Rationale: Treatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer, CORM-2) or a classical heme oxygenase 1 inducer (cobalt protoporphyrin IX, CoPP) has potent anti-inflammatory effects, but the role played by these treatments in the antinociceptive effects of morphine during acute and chronic pain was not evaluated.

Objectives: In wild type (WT), neuronal (NOS1-KO), or inducible (NOS2-KO) nitric oxide synthases knockout mice, we evaluated the effects of CORM-2 and CoPP treatments in the antinociceptive actions of morphine and their interaction with nitric oxide during acute, visceral, and chronic inflammatory or neuropathic pain.

Methods: Acute and visceral pain was assessed through formalin and acid acetic writhing tests. Chronic inflammatory pain induced by the intra-articular administration of complete Freund's adjuvant and neuropathic pain by partial ligation of sciatic nerve were evaluated by measuring allodynia and hyperalgesia using the von Frey filaments, plantar, or cold plate tests.

Results: While nitric oxide, synthetized by NOS1 and/or NOS2, increased the local antinociceptive effects of morphine during acute and chronic pain, it decreased the inhibitory effects of morphine after visceral pain. Moreover, while CORM-2 or CoPP treatments did not alter or reduced the antinociceptive effects of morphine during acute and visceral pain, both treatments improved the local antiallodynic and antihyperalgesic effects of morphine after chronic inflammatory or neuropathic pain in WT, but not in KO mice.

Conclusions: CORM-2 and CoPP treatments improved the local antinociceptive effects of morphine during chronic inflammatory and neuropathic pain by interaction with nitric oxide synthetized by NOS1 and NOS2 isoforms.