HO-CO pathway activation may be associated with hippocampal µ and δ opioid receptors in inhibiting inflammatory pain aversiveness and nociception in WT but not NOS2-KO mice.

Carbon monoxide (CO) and nitric oxide (NO) modulate inflammatory nociception and anxiety. We evaluate whether treatments with a heme oxygenase-1 (HO-1) inducer (CoPP) or a carbon monoxide-releasing molecule (CORM-2) are capable of inhibiting inflammatory pain aversiveness in wild type (WT) and inducible nitric oxide synthase-knock out (NOS2-KO) mice with persistent inflammation and its relationship with µ- (MOR) and δ- (DOR) opioid receptors. WT and NOS2-KO male mice with complete Freund's adjuvant (CFA) injected into the hind paw were evaluated in the von Frey and the escape-avoidance paradigm (PEAP) tests, at 10 days, before and after the treatment with CORM-2 (5 mg/kg) or CoPP (2.5 mg/kg). WT mice groups treated with CORM-2 or CoPP also received naloxone (NLX, a non-specific opioid receptor antagonist). The HO-1, neuronal nitric oxide synthase, NOS2, MOR, and DOR expression in the dorsal hippocampus were evaluated by western blot. CFA reduced mechanical threshold in WT and NOS2-KO mice but only increased the percentage of time in the light compartment in the PEAP in WT mice. CORM-2 and CoPP inhibited these effects in both strains. Pre-treatment with NLX reverses the anti-allodynic and anti-aversive effects of CORM-2 or CoPP in WT mice. CORM-2 and CoPP increases the protein levels of HO-1, MOR and DOR in the dorsal hippocampus of WT mice but not in NOS2-KO animals. Results showed that HOCO pathway activation promotes anti-allodynic effects and reduced pain aversiveness caused by peripheral inflammation by increasing the expression of MOR and DOR activated by HO-1 in the dorsal hippocampus.