Treatment with carbon monoxide-releasing molecules and an HO-1 inducer enhances the effects and expression of µ-opioid receptors during neuropathic pain.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Universitat Autònoma de Barcelona, Barcelona, Spain.
Arnau
A
Hervera
Sergi
S
Leánez
Roberto
R
Motterlini
Olga
O
Pol
D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000627:therapeutic use*; D003251:Constriction, Pathologic / Q000150:complications; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000627:therapeutic use; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006358:Hot Temperature; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D009942:Organometallic Compounds / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D011524:Protoporphyrins / Q000627:therapeutic use; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000096:biosynthesis / Q000187:drug effects*
D000701:Analgesics, Opioid; D007211:Indoles; D009942:Organometallic Compounds; D011524:Protoporphyrins; D043885:Receptor, Cannabinoid, CB2; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C476530:tricarbonylchloro(glycinato)ruthenium(II); C447082:tricarbonyldichlororuthenium (II) dimer; C007095:cobaltiprotoporphyrin; D009020:Morphine; D002248:Carbon Monoxide; D020881:Enkephalin, D-Penicillamine (2,5)-; D051547:Heme Oxygenase-1; C402944:JHW 015