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

Chang Z. Zhu, Sonya G. Wilson, Joseph P. Mikusa, Carol T. Wismer, Donna M. Gauvin, James J. Lynch, Carrie L. Wade, Michael W. Decker, Prisca Honore

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93 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)107-118
Number of pages12
JournalEuropean Journal of Pharmacology
Volume506
Issue number2
DOIs
StatePublished - Dec 15 2004

Keywords

  • Allodynia
  • Glutamate
  • Hyperalgesia
  • MPEP
  • MTEP
  • Modality

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    Zhu, C. Z., Wilson, S. G., Mikusa, J. P., Wismer, C. T., Gauvin, D. M., Lynch, J. J., Wade, C. L., Decker, M. W., & Honore, P. (2004). Assessing the role of metabotropic glutamate receptor 5 in multiple nociceptive modalities. European Journal of Pharmacology, 506(2), 107-118. https://doi.org/10.1016/j.ejphar.2004.11.005