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

• Published in: European journal of pharmacology 2004-12, Vol.506 (2), p.107-118
• Main Authors: Zhu, Chang Z., Wilson, Sonya G., Mikusa, Joseph P., Wismer, Carol T., Gauvin, Donna M., Lynch, James J., Wade, Carrie L., Decker, Michael W., Honore, Prisca
• Format: Article
• Language: English
• Subjects: Acetic Acid; Allodynia; Animals; Biological and medical sciences; Carrageenan; Central Nervous System - physiology; Constriction, Pathologic - pathology; Edema - chemically induced; Formaldehyde; Glutamate; Hyperalgesia; Hyperalgesia - chemically induced; Male; Medical sciences; Mice; Mice, Inbred ICR; Modality; Motor Activity - drug effects; MPEP; MTEP; Pain - chemically induced; Pain - physiopathology; Pain - psychology; Pain Measurement - drug effects; Pain, Postoperative - pathology; Pharmacology. Drug treatments; Psychomotor Performance - drug effects; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - drug effects; Receptors, Metabotropic Glutamate - physiology; Spinal Nerves - pathology; Thiazoles - pharmacology; Vincristine - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2004.11.005

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.