Group III mGluR8 negatively modulates TRP channels

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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. The following studies used a multifaceted approach to examine the interaction between group III mGluRs (mGluR8) and two TRP channels: TRPV1 and TRPA1. In the first study, we examined the interaction between group III mGluRs and TRPV1. Anatomical studies demonstrated that group III mGluR8 is expressed on cutaneous axons and is co-localized with TRPV1 in the dorsal root ganglia (DRG). In behavior studies, peripheral activation of group III mGluRs had no effect on paw withdrawal latency (PWL) to heat in naïve rats. However, local peripheral activation of group III mGluRs significantly attenuated capsaicin (CAP, TRPV1 agonist)-induced lifting/licking and reduced flinching behavior. Finally peripheral group III mGluR activation reversed forskolin (FSK)-induced heat sensitivity, suggesting that group III could modulate TRPV1 by down-regulating cAMP-PKA activity. In the second part of the study, we examined the interaction between group III mGluR8 and TRPA1. Ca2+ imaging studies demonstrated co-localization and functional coupling of TRPA1 and mGluR8, since DCPG (mGluR8 agonist) significantly reduced the number of mustard oil (MO, TRPA1 agonist) responsive cells. Behavioral studies demonstrated that peripheral DCPG reversed the MO-induced decrease in PWT. At the single fiber level, DCPG significantly attenuated MO-induced nociceptor activity and reversed the MO-induced decrease in mechanical threshold. Furthermore, DCPG significantly reduced the number of MO-induced mechanically sensitive fibers. Inhibition of PKA using RpCAMPS significantly reduced MO-induced calcium mobilization and there was a trend to reduce the number of MO-responsive cells. Taken together, these results show that group III mGluRs can negatively modulate TRPV1 and TRPA1 activity. Furthermore, it is likely that this modulation occurs at the level of the cAMP/PKA pathway. Additionally, these studies demonstrate that group III agonists may be effective in treatment of mechanical allodynia which can develop as a result of inflammation, nerve injury, chemotherapy or other disease states.

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mGluR8, TRPV1, TRPA1
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