Group III mGluR8 negatively modulates TRPA1

Several lines of evidence indicate group III metabotropic glutamate receptors (mGluRs) have systemic anti-hyperalgesic effects. We hypothesized this could occur through modulation of TRP channels on nociceptors. This study used a multifaceted approach to examine the interaction between group III mGluRs (mGluR8) and transient receptor potential ankyrin 1 (TRPA1) on cutaneous nociceptors in rats. Ca²⁺ imaging studies demonstrated co-localization and functional coupling of TRPA1 and mGluR8, since 1μM (S)-3,4-dicarboxyphenylglycine (DCPG) (mGluR8 agonist) significantly reduced Ca²⁺ mobilization produced by 30μM mustard oil (MO), a TRPA1 agonist. Behavioral studies demonstrated that 10mM MO produced mechanical hypersensitivity when topically applied to the hind paw, significantly decreasing paw withdrawal threshold (PWT) from 15g to 6g. However, administration of 30μM DCPG prior to 10mM MO reversed this hypersensitivity such that PWT was not significantly different from baseline. At the single-fiber level, compared to vehicle, 30μM MO significantly increased nociceptor activity and decreased mechanical threshold. However, 30μM DCPG reversed both of these MO-induced effects. Furthermore, DCPG significantly reduced the number of MO-induced mechanically sensitive fibers. Inhibition of protein kinase A (PKA) using Rp-cyclic 3',5'-hydrogen phosphorothioate adenosine triethylammonium salt (RpCAMPS) (PKA inhibitor, 1 and 10μM) significantly reduced MO-induced Ca²⁺ mobilization. Taken together, these results show that group III mGluRs negatively modulate TRPA1 activity on cutaneous nociceptors. Furthermore, it is likely that this modulation occurs intracellularly at the level of the cAMP/PKA pathway. This study demonstrates that group III agonists may be effective in the treatment of mechanical hypersensitivity which can develop as a result of inflammation, nerve injury, chemotherapy and other disease states.