Reversal of carrageenan-induced hypersensitivity by the metabotropic glutamate receptor 7 agonist AMN082 in rats

Mark D. Gunn1, Andrea M. Nolan1, Claire Crossan1, Sharron Dolan2 1Division of Cell Sciences, University of Glasgow, Glasgow G61 1QH; 2Department of Biological & Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA.

Metabotropic glutamate (mGlu) receptor activity contributes to spinal nociceptive processing and inflammatory hyperalgesia, however, the specific role of group III mGlu receptors in pain processing remains elusive. Investigating the role of specific group III mGlu receptor subtypes has proved problematic due to a lack of subtype selective compounds. Recently, a novel systemically active mGlu7 receptor selective agonist, N,N`-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) has been described (Mitsukawa et al., 2005). The aim of this study was to evaluate the contribution of mGlu7 receptor activity to altered nociceptive processing in a model of acute inflammatory pain (intradermal carrageenen) in rats.

Carrageenan (3%; 50μl) was injected intradermally into the right hindpaw of adult male Sprague-Dawley rats (n = 8/group; 250-300g) and the effects of intraperitoneal administration of AMN082 (1 or 5 mgkg-1) or drug-vehicle on hindpaw hypersensitivity measured. Drugs were administered 3 hours post-carrageenan. Mechanical response thresholds (in grams) and thermal response latency (in seconds) to hindpaw stimulation were measured before and 2, 4, 6 and 24 h post-carrageenan injection. The maximum effect (Emax) was calculated as the maximum change in withdrawal threshold after carrageenan injection from baseline responses. Data (mean ± SEM) were analysed using ANOVA with post-hoc Tukey’s test.

Maximum thermal and mechanical hypersensitivity were observed 6 h post-carrageenan (Emax: 53.6 ± 9.0% and 45.3 ± 10.0%, respectively). Treatment with 1 and 5 mgkg-1 AMN082 reversed carrageenan-induced thermal hypersensitivity at 6 hours (Emax: -2.2 ± 15%; p < 0.01 and 10.7 ± 19.1%; p < 0.05, respectively). Only low dose AMN082 (1 mgkg-1) significantly attenuated mechanical hypersensitivity at 6 hours (Emax: 22.3 ± 7.1%; p < 0.05). AMN082 had no effect on acute nociceptive responses in normal animals.

This study showed that systemic administration of AMN082 blocked thermal and mechanical hypersensitivity induced by carrageenan. These findings suggest that activity at mGlu7 receptors may contribute to alleviation of inflammatory hyperalgesia in rats. Consequently, mGlu7 receptors may be effective therapeutic targets for relief of post-injury hypersensitivity and pain.

Mitsukawa, K., Yamamoto, R., Ofner, S., Nozulak, J., Pescott, O., Lukic, S., Stoehr, N., Mombereau, C., Kuhn, R., McAllister, K.H., Van Der Putten, H. (2005) Proceedings of the National Academy of Sciences of the United States of America 102, 18712-18717.

This study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC).