Assessing the role of metabotropic glutamate receptor 5 in multiple nociceptive modalities.

Abstract

Preclinical data, performed in a limited number of pain models, suggest that functional blockade of metabotropic glutamate (mGlu) receptors may be beneficial for pain management. In the present study, effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective mGlu5 receptor antagonist, were examined in a wide variety of rodent nociceptive and hypersensitivity models in order to fully characterize the potential analgesic profile of mGlu5 receptor blockade. Effects of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), as potent and selective as MPEP at mGlu5/mGlu1 receptors but more selective than MPEP at N-methyl-aspartate (NMDA) receptors, were also evaluated in selected nociceptive and side effect models. MPEP (3-30 mg/kg, i.p.) produced a dose-dependent reversal of thermal and mechanical hyperalgesia following complete Freund's adjuvant (CFA)-induced inflammatory hypersensitivity. Additionally, MPEP (3-30 mg/kg, i.p.) decreased thermal hyperalgesia observed in carrageenan-induced inflammatory hypersensitivity without affecting paw edema, abolished acetic acid-induced writhing activity in mice, and was shown to reduce mechanical allodynia and thermal hyperalgesia observed in a model of post-operative hypersensitivity and formalin-induced spontaneous pain. Furthermore, at 30 mg/kg, i.p., MPEP significantly attenuated mechanical allodynia observed in three neuropathic pain models, i.e. spinal nerve ligation, sciatic nerve constriction and vincristine-induced neuropathic pain. MTEP (3-30 mg/kg, i.p.) also potently reduced CFA-induced thermal hyperalgesia. However, at 100 mg/kg, i.p., MPEP and MTEP produced central nerve system (CNS) side effects as measured by rotarod performance and exploratory locomotor activity. These results suggest a role for mGlu5 receptors in multiple nociceptive modalities, though CNS side effects may be a limiting factor in developing mGlu5 receptor analgesic compounds.

• Authors: Chang Z Zhu, Sonya G Wilson, Joseph P Mikusa, Carol T Wismer, Donna M Gauvin, James J Lynch 3rd, Carrie L Wade, Michael W Decker, Prisca Honore
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 506 Issue 2 Pg. 107-18 (Dec 15 2004) ISSN: 0014-2999 [Print] Netherlands
• PMID: 15588730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine
• Pyridines
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate
• Thiazoles
• metabotropic glutamate receptor type 1
• Formaldehyde
• Vincristine
• 6-methyl-2-(phenylethynyl)pyridine
• Carrageenan
• Acetic Acid

Topics

• Acetic Acid
• Animals
• Carrageenan
• Central Nervous System (physiology)
• Constriction, Pathologic (pathology)
• Edema (chemically induced)
• Formaldehyde
• Hyperalgesia (chemically induced)
• Male
• Mice
• Mice, Inbred ICR
• Motor Activity (drug effects)
• Pain (chemically induced, physiopathology, psychology)
• Pain Measurement (drug effects)
• Pain, Postoperative (pathology)
• Psychomotor Performance (drug effects)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate (drug effects, physiology)
• Spinal Nerves (pathology)
• Thiazoles (pharmacology)
• Vincristine (pharmacology)