Trends in Neurosciences
Volume 24, Issue 10, 1 October 2001, Pages 550-552
Journal home page for Trends in Neurosciences

Research update
Peripheral metabotropic glutamate receptors: fight the pain where it hurts

https://doi.org/10.1016/S0166-2236(00)02007-5Get rights and content

Abstract

Recent anatomical and behavioral data show the expression of G-protein coupled metabotropic glutamate receptors in the periphery on nociceptive primary afferent nerve terminals, and provide evidence for a functional role of peripheral metabotropic glutamate receptors in inflammatory pain. These findings have important implications for new therapeutic strategies that target peripheral metabotropic glutamate receptors for pain relief. They also alert us to the necessity of assessing drug effects at different levels of the nervous system: peripheral and central.

Section snippets

Anatomical evidence for peripheral mglu receptors

Gereau and colleagues 10 show at the electron microscopic level that mglu1 and mglu5 subtypes are constitutively expressed on 9% and 16%, respectively, of the unmyelinated axons at the dermal-epidermal junction of mouse hind paw. Based on previous work by Carlton 9 and others 16 it is conceivable that in the skin, mglu receptors are predominantly localized on nociceptive primary afferents. Understanding the role and mechanisms of peripheral mglu receptor-mediated events requires further

Functional relevance of peripheral mglu receptors in normal nociception

Gereau and colleagues 10 report for the first time that exogenous activation of either mglu1 or mglu5 affects normal nociception in mice. Activation of mglu1 and mglu5 by the subcutaneous injection of a group I agonist (DHPG; S-3,5-dihydroxyphenylglycine) produced long-lasting (∼3 hrs) thermal hypersensitivity, which was reduced by subcutaneous injections of mglu1 antagonists [CPCCOEt; 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester and LY367385; (S

Functional role of peripheral mglu receptors in inflammatory pain

Gereau's study 10 is the first to show the crucial involvement of peripheral mglu1 and mglu5 in prolonged pain. Intradermal injections of either mglu1 or mglu5 antagonists (CPCCOEt and MPEP, respectively) inhibit the second, but not the first, phase of the formalin pain test. The first phase represents acute nociception caused by primary afferent activation, whereas the second phase reflects a combination of peripheral and central sensitization 17, 18.

The following observations support the

Clinical implications and conclusions

The studies by Gereau and colleagues 10 and Walker et al.16 suggest that peripherally acting group I mglu receptor antagonists might become useful novel drugs in the treatment of inflammatory pain while avoiding possible central side effects. Some notes of caution should be added. Anti-nociceptive effects of mglu receptor antagonists in the periphery have been assessed only in the relatively acute phases of inflammatory pain models. At more-chronic stages CNS changes could dominate while the

Acknowledgements

V.N. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) Grants NS-38261 and NS-11255. Thanks to W.D. Willis for critical reading of and helpful comments on the manuscript.

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