Trends in Neurosciences
Research updatePeripheral metabotropic glutamate receptors: fight the pain where it hurts
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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