Highlights
- •Activation of mGlu1/5 leads to phosphorylation of serine-800 of TRPV1 in primary afferents.
- •Peripheral mGlu1/5 activation leads to TRPV1 sensitization and muscle hyperalgesia via PKC.
- •AKAP150 is involved in mGlu1/5-mediated mechanical hyperalgesia in the muscle.
Abstract
Elevated glutamate levels within injured muscle play important roles in muscle pain
and hyperalgesia. In this study, we hypothesized that protein kinase C (PKC)–dependent
TRPV1 phosphorylation contributes to the muscle mechanical hyperalgesia following
activation of Group I metabotropic glutamate receptors (mGlu1/5). Mechanical hyperalgesia
induced by (R,S)-3,5-dihydroxyphenylglycine (DHPG), an mGlu1/5 agonist, in the masseter muscle was
attenuated by AMG9810, a specific TRPV1 antagonist. AMG9810 also suppressed mechanical
hyperalgesia evoked by pharmacologic activation of PKC. DHPG-induced mechanical hyperalgesia
was suppressed by pretreatment with a decoy peptide that disrupted interactions between
TRPV1 and A-kinase–anchoring protein (AKAP), which facilitates phosphorylation of
TRPV1. In dissociated trigeminal ganglia, DHPG upregulated serine phosphorylation
of TRPV1 (S800), during which DHPG-induced mechanical hyperalgesia was prominent.
The TRPV1 phosphorylation at S800 was suppressed by a PKC inhibitor. Electrophysiologic
measurements in trigeminal ganglion neurons demonstrated that TRPV1 sensitivity was
enhanced by pretreatment with DHPG, and this was prevented by a PKC inhibitor, but
not by a protein kinase A inhibitor. These results suggest that mGlu1/5 activation
in masseter afferents invokes phosphorylation of TRPV1 serine residues including S800,
and that phosphorylation-induced sensitization of TRPV1 is involved in masseter mechanical
hyperalgesia. These data support a role of TRPV1 as an integrator of glutamate receptor
signaling in muscle nociceptors.
Perspective
This article demonstrates that activation of mGlu1/5 leads to phosphorylation of a
specific TRPV1 residue via PKC and AKAP150 in trigeminal sensory neurons and that
functional interactions between glutamate receptors and TRPV1 mediate mechanical hyperalgesia
in the muscle tissue.
Key words
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Article info
Publication history
Published online: November 01, 2014
Accepted:
October 21,
2014
Received in revised form:
October 2,
2014
Received:
May 28,
2014
Footnotes
This study was supported by National Institutes of Health grants R01 DE016062 (J.Y.R.) and R01 DE023846 (M.-K.C). The authors disclose no conflict of interest in respect to this work.
Identification
Copyright
© 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
