jhw-015 and cobaltiprotoporphyrin

The activation of cannabinoid 2 receptors (CB2R) attenuates chronic pain, but the role played by carbon monoxide synthesized by the inducible heme oxygenase 1 (HO-1) on the anti-nociceptive effects produced by a selective CB2R agonist, JWH-015, during painful diabetic neuropathy remains unknown.. In streptozotocin (STZ)-induced diabetic mice, the anti-allodynic and anti-hyperalgesic effects of the subcutaneous administration of JWH-015 alone or combined with the intraperitoneal administration of a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer (CORM-2)) or an HO-1 inducer compound (cobalt protoporphyrin IX (CoPP)) at 10 mg/kg were evaluated. Reversion of JWH-015 anti-nociceptive effects by the administration of an HO-1 inhibitor (tin protoporphyrin IX (SnPP)) and a CB2R antagonist (AM630) was also evaluated. Furthermore, the protein levels of HO-1, neuronal nitric oxide synthase (NOS1), and CB2R in diabetic mice treated with CORM-2 and CoPP alone or combined with JWH-015 were also assessed.. The administration of JWH-015 dose dependently inhibited hypersensitivity induced by diabetes. The effects of JWH-015 were enhanced by their coadministration with CORM-2 or CoPP and reversed by SnPP or AM630. The increased protein levels of HO-1 induced by CORM-2 and CoPP treatments were further enhanced in JWH-015-treated mice. All treatments similarly enhanced the peripheral expression of CB2R and avoided the spinal cord over-expression of NOS1 induced by diabetes.. The activation of HO-1 enhanced the anti-nociceptive effects of JWH-015 in diabetic mice, suggesting that coadministration of JWH-015 with CORM-2 or CoPP might be an interesting approach for the treatment of painful diabetic neuropathy in mice.

Topics: Analgesics; Animals; Carbon Monoxide; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Induction; Heme Oxygenase-1; Hyperalgesia; Indoles; Male; Metalloporphyrins; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type I; Organometallic Compounds; Protoporphyrins; Receptor, Cannabinoid, CB2; Spinal Cord

The administration of µ-opioid receptors (MOR) and δ-opioid receptors (DOR) as well as cannabinoid-2 receptor (CB2R) agonists attenuates neuropathic pain. We investigated if treatment with two carbon monoxide-releasing molecules (CORM-2 and CORM-3) or an inducible heme oxygenase inducer (cobalt protoporphyrin IX, CoPP) could modulate the local and systemic effects and expression of MOR, DOR, and CB2R during neuropathic pain.. In C57BL/6 mice, at 10 days after the chronic constriction of sciatic nerve, we evaluated the effects of the intraperitoneal administration of 10 mg/kg of CORM-2, CORM-3, or CoPP on the antiallodynic and antihyperalgesic actions of a locally or systemically administered MOR (morphine), DOR ([d-Pen(2),d-Pen(5)]-enkephalin) or CB2R ((2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone ) agonist. The effects of CORM-2 and CoPP treatments on the expression of MOR, DOR, CB2R, inducible and constitutive heme oxygenases, microglia activation marker (CD11b/c), and neuronal and inducible nitric oxide synthases were also assessed.. Treatments with CO-RMs and CoPP reduced the mechanical and thermal hypersensitivity induced by sciatic nerve injury, increased the local, but not systemic, antinociceptive effects of morphine, and decreased those produced by DPDPE and JWH-015. Both CORM-2 and CoPP treatments enhanced MOR and inducible heme oxygenase expression, unaltered DOR and constitutive heme oxygenase expression, and decreased the overexpression of CB2R, CD11b/c, and neuronal and inducible nitric oxide synthases induced by sciatic nerve injury.. This study shows that CO-RMs and CoPP treatments increase the local antinociceptive effects of morphine through enhancing MOR peripheral expression and inhibiting spinal microglial activation and overexpression of neuronal/inducible nitric oxide synthases.

Topics: Analgesics, Opioid; Animals; Carbon Monoxide; Constriction, Pathologic; Enkephalin, D-Penicillamine (2,5)-; Enzyme Induction; Heme Oxygenase-1; Hot Temperature; Indoles; Male; Mice; Mice, Inbred C57BL; Morphine; Neuralgia; Organometallic Compounds; Pain Measurement; Physical Stimulation; Protoporphyrins; Receptor, Cannabinoid, CB2; Receptors, Opioid, delta; Receptors, Opioid, mu