Elsevier

Neuroscience

Volume 154, Issue 2, 23 June 2008, Pages 754-766
Neuroscience

Pain mechanism
Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

https://doi.org/10.1016/j.neuroscience.2008.03.084Get rights and content

Abstract

Several lines of evidence indicate that Group II metabotropic glutamate receptor (mGluR) activation can depress sensory transmission. We have reported the expression of Group II mGluRs on unmyelinated axons, many of which were presumed to be nociceptors, in the rat digital nerve [Carlton SM, Hargett GL, Coggeshall RE (2001b) Localization of metabotropic glutamate receptors 2/3 on primary afferent axons in the rat. Neuroscience 105:957–969]. The goals of the present study are to further our understanding of Group II modulation of nociceptor processing in the periphery, documenting behavioral changes using inflammatory models and documenting, for the first time, cutaneous single fiber activity following exposure to a Group II agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) and antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495, LY). The data indicate that peripheral Group II mGluR activation does not depress nociceptive behaviors or nociceptor fiber responses in the non-sensitized state (i.e. following brief nociceptive mechanical or thermal stimulation) but can depress these responses when nociceptors are sensitized by exposure to formalin or inflammatory soup. Group II mGluR agonist-induced inhibition can be blocked by a selective Group II antagonist. Peripheral Group II mGluR-induced inhibition evoked in these studies occurs through activation of local receptors and not through spinal or supraspinal mechanisms. The data indicate that administration of selective Group II agonists may be potent therapeutic agents for prevention of peripheral sensitization and for treatment of inflammatory pain.

Section snippets

Experimental procedures

All experiments were approved by the University Animal Care and Use Committee and followed the IASP guidelines for the ethical care and use of laboratory animals (Zimmermann, 1983). Steps were taken to minimize both the number of animals and their discomfort. All rats were male, Sprague–Dawley (250–300 g) obtained from Harlan, Indianapolis, IN, USA.

Group II mGluR modulation of mechanical and thermal sensitivity

Intraplantar injection of 0.1 μM or 100 μM APDC in normal rats did not affect baseline thermal sensitivity, inducing no change in PWL compared with vehicle over the subsequent 40 min testing period (Fig. 1A). Similarly, intraplantar injection of either 0.1 μM or 100 μM APDC did not affect mechanical sensitivity, inducing no change in PWT compared with vehicle (Fig. 1B). The results suggest that APDC in this range does not modulate behavioral responses to acute thermal or mechanical stimulation

Discussion

These studies demonstrate several key aspects of peripheral Group II mGluR function. Activation of peripheral Group II mGluRs 1) does not depress nociceptive behavioral responses or nociceptor activity in the non-sensitized state (i.e. following brief nociceptive mechanical or thermal stimulation), 2) can depress these responses when the nociceptors are sensitized by inflammation, 3) can produce an inhibitory effect through local receptor activation that can be blocked by a local Group II

Conclusions

The results presented here demonstrate that Group II activation has no effect on normal (non-sensitized) nociceptor function. In contrast, when conditions arise where CMH nociceptors are sensitized by inflammatory mediators, activation of peripheral Group II mGluRs can dramatically reduce evoked nociceptive behaviors, and importantly, can effectively inhibit inflammatory mediator-induced excitation and sensitization, indicating that Group II mGluR activation is anti-hyperalgesic. Group II

Acknowledgments

The authors would like to thank Ms. Lyn Schilling for her assistance in preparing this manuscript. This work was supported by NIH grants NS27910, NS40700 and NS54765 to S.M.C.

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