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 &dgr;-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.

[1]  O. Pol,et al.  The inhibition of the nitric oxide-cGMP-PKG-JNK signaling pathway avoids the development of tolerance to the local antiallodynic effects produced by morphine during neuropathic pain. , 2012, European journal of pharmacology.

[2]  O. Pol,et al.  T264 POTENTIAL THERAPEUTIC ROLE OF CARBON MONOXIDE SYNTHESIZED BY HEME OXYGENASE-1 IN THE ATTENUATION OF NEUROPATHIC PAIN VIA MICROGLIAL CELLS INACTIVATION , 2011 .

[3]  W. Fan,et al.  Carbon monoxide: A gas that modulates nociception , 2011, Journal of neuroscience research.

[4]  D. Filliol,et al.  Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia , 2011, PAIN.

[5]  O. Pol,et al.  Peripheral effects of morphine and expression of μ-opioid receptors in the dorsal root ganglia during neuropathic pain: nitric oxide signaling , 2011, Molecular pain.

[6]  O. Pol,et al.  The Role of Nitric Oxide in the Local Antiallodynic and Antihyperalgesic Effects and Expression of δ-Opioid and Cannabinoid-2 Receptors during Neuropathic Pain in Mice , 2010, Journal of Pharmacology and Experimental Therapeutics.

[7]  M. Alcaraz,et al.  The CO-releasing molecule CORM-3 protects against articular degradation in the K/BxN serum transfer arthritis model. , 2010, European journal of pharmacology.

[8]  M. Korostyński,et al.  Differential activation of spinal microglial and astroglial cells in a mouse model of peripheral neuropathic pain. , 2009, European journal of pharmacology.

[9]  A. Cuadrado,et al.  Haeme oxygenase-1 overexpression via nAChRs and the transcription factor Nrf2 has antinociceptive effects in the formalin test , 2009, PAIN.

[10]  A. I. Rojo,et al.  Heme oxygenase-1 induction modulates microsomal prostaglandin E synthase-1 expression and prostaglandin E(2) production in osteoarthritic chondrocytes. , 2009, Biochemical pharmacology.

[11]  M. Korostyński,et al.  Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and inflammatory pain , 2009, PAIN.

[12]  H. Toda,et al.  Modulation of Opioid Actions by Nitric Oxide Signaling , 2009, Anesthesiology.

[13]  L. Leybaert,et al.  Water-soluble CO-releasing molecules reduce the development of postoperative ileus via modulation of MAPK/HO-1 signalling and reduction of oxidative stress , 2008, Gut.

[14]  M. Alcaraz,et al.  The CO-releasing molecule CORM-2 is a novel regulator of the inflammatory process in osteoarthritic chondrocytes. , 2008, Rheumatology.

[15]  R. Meyer,et al.  Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury , 2008, PAIN.

[16]  A. I. Rojo,et al.  Nrf2-mediated haeme oxygenase-1 up-regulation induced by cobalt protoporphyrin has antinociceptive effects against inflammatory pain in the formalin test in mice , 2008, PAIN®.

[17]  D. Fink,et al.  Continuous δ-Opioid Receptor Activation Reduces Neuronal Voltage-Gated Sodium Channel (NaV1.7) Levels through Activation of Protein Kinase C in Painful Diabetic Neuropathy , 2008, The Journal of Neuroscience.

[18]  J. Deleo,et al.  Spinal Microglial and Perivascular Cell Cannabinoid Receptor Type 2 Activation Reduces Behavioral Hypersensitivity without Tolerance after Peripheral Nerve Injury , 2008, Anesthesiology.

[19]  M. Alcaraz,et al.  Treatment with a CO-releasing molecule (CORM-3) reduces joint inflammation and erosion in murine collagen-induced arthritis , 2007, Annals of the rheumatic diseases.

[20]  B. Przewłocka,et al.  Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain. , 2007, European journal of pharmacology.

[21]  R. Przewłocki,et al.  Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat. , 2007, European journal of pharmacology.

[22]  L. Branco,et al.  Role of the peripheral heme oxygenase-carbon monoxide pathway on the nociceptive response of rats to the formalin test: evidence for a cGMP signaling pathway. , 2007, European journal of pharmacology.

[23]  C. Cahill,et al.  Anti-allodynic effects of peripheral delta opioid receptors in neuropathic pain , 2007, Pain.

[24]  C. Green,et al.  Modulation of Thrombin-Induced Neuroinflammation in BV-2 Microglia by Carbon Monoxide-Releasing Molecule 3 , 2006, Journal of Pharmacology and Experimental Therapeutics.

[25]  O. Valverde,et al.  Expression of opioid receptors and c-fos in CB1 knockout mice exposed to neuropathic pain , 2006, Neuropharmacology.

[26]  L. Joosten,et al.  Influence of heme oxygenase 1 modulation on the progression of murine collagen-induced arthritis. , 2005, Arthritis and rheumatism.

[27]  R. Foresti,et al.  Carbon monoxide‐releasing molecules (CO‐RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages , 2005, British journal of pharmacology.

[28]  R. Przewłocki,et al.  Local peripheral effects of μ-opioid receptor agonists in neuropathic pain in rats , 2004, Neuroscience Letters.

[29]  R. N. Takahashi,et al.  Synergistic interaction between mazindol, an anorectic drug, and swim-stress on analgesic responses in the formalin test in mice , 2004, Neuroscience Letters.

[30]  M. L. Sotgiu,et al.  Repeated treatment with the synthetic cannabinoid WIN 55,212‐2 reduces both hyperalgesia and production of pronociceptive mediators in a rat model of neuropathic pain , 2004, British journal of pharmacology.

[31]  G. Lighthall,et al.  Heme oxygenase type 2 modulates behavioral and molecular changes during chronic exposure to morphine , 2003, Neuroscience.

[32]  P. Naughton,et al.  Cardioprotective Actions by a Water‐Soluble Carbon nMonoxide‐Releasing Molecule , 2003, Circulation research.

[33]  T. Groblewski,et al.  Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models , 2003, The European journal of neuroscience.

[34]  D. Zochodne,et al.  μ Opioid receptors and analgesia at the site of a peripheral nerve injury , 2003 .

[35]  J. Clark,et al.  Heme oxygenase type 2 participates in the development of chronic inflammatory and neuropathic pain. , 2003, The journal of pain : official journal of the American Pain Society.

[36]  Y. Uresin,et al.  Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia, tolerance and dependence in mice. , 2003, Life Science.

[37]  D. Zochodne,et al.  Mu opioid receptors and analgesia at the site of a peripheral nerve injury. , 2003, Annals of neurology.

[38]  P. Sarathchandra,et al.  Carbon Monoxide-Releasing Molecules: Characterization of Biochemical and Vascular Activities , 2002, Circulation research.

[39]  J. Clark,et al.  Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. , 2001, Brain research. Molecular brain research.

[40]  Steven F. Maier,et al.  Glial activation: a driving force for pathological pain , 2001, Trends in Neurosciences.

[41]  F. Cunha,et al.  Role of the haeme oxygenase/carbon monoxide pathway in mechanical nociceptor hypersensitivity , 2001, British journal of pharmacology.

[42]  J. Clark,et al.  The Role of Heme Oxygenase in Neuropathic and Incisional Pain , 2000, Anesthesia and analgesia.

[43]  J. Westman,et al.  Spinal nerve lesion induces upregulation of constitutive isoform of hemeoxygenase in the spinal cord. An immunohistochemical investigation in therat. , 2000 .

[44]  R. Przewłocki,et al.  Inhibition of nitric oxide synthase enhances antinociception mediated by mu, delta and kappa opioid receptors in acute and prolonged pain in the rat spinal cord. , 1997, The Journal of pharmacology and experimental therapeutics.

[45]  T. Yaksh,et al.  Quantitative assessment of tactile allodynia in the rat paw , 1994, Journal of Neuroscience Methods.

[46]  Gary J. Bennett,et al.  A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man , 1988, Pain.

[47]  R. Dubner,et al.  A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia , 1987, Pain.