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

• Published in: Brain research bulletin 2021-04, Vol.169, p.8-17
• Main Authors: Cazuza, Rafael A., Arantes, Ana Luisa F., Pol, Olga, Leite-Panissi, Christie R.A.
• Format: Article
• Language: English
• Subjects: Animals; Avoidance Learning - physiology; Carbon monoxide; Carbon Monoxide - metabolism; Heme oxygenase; Heme Oxygenase (Decyclizing) - metabolism; Hippocampus - drug effects; Hippocampus - metabolism; Inflammatory pain; Male; Mice; Mice, Knockout; Nitric oxide; Nociception - physiology; Opioid receptors; Organometallic Compounds - pharmacology; Pain - metabolism; Pain aversiveness; Pain Measurement; Pyrazines - pharmacology; Pyrroles - pharmacology; Receptors, Opioid, delta - metabolism; Receptors, Opioid, mu - metabolism; Signal Transduction - drug effects
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2021.01.002

•CO-induced analgesia can be due to μ and δ opioid receptors activation.•HO−CO pathway activation produces an anti-allodynic and anti-aversive effects.•HO-1 upregulation increases the expression of opioid receptors in the hippocampus. 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.