Phosphorylation of TRPV1 S801 Contributes to Modality-Specific Hyperalgesia in Mice

Joseph, John; Qu, Lintao; Wang, Sheng; Kim, Martin; Bennett, Daniel J.; Ro, Jin Y.; Chung, Man‐Kyo

doi:10.1523/jneurosci.1064-19.2019

Cited by 53 publications

(53 citation statements)

References 44 publications

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“…NMDA increases PKC-dependent phosphorylation of TRPV1 serine 800 residue (TRPV1 S800) in dissociated trigeminal neurons, suggesting that TRPV1 S800 phosphorylation is a convergent pathway in the glutamate-induced regulation of TRPV1 (Lee, Chung, and Ro 2012). In a mouse line in which TRPV1 S801, an orthologue residue of rat TRPV1 S800, is mutated into alanine to prevent phosphorylation, mouse grimace scale (MGS) following masseteric CFA injection is attenuated as compared with wild-type mice, suggesting that TRPV1 S801 phosphorylation-dependent mechanisms contribute to CFA-induced spontaneous pain (Joseph et al 2019).…”

Section: Primary Afferents For Acute and Chronic Craniofacial Muscle mentioning

confidence: 99%

“…Nonpeptidergic masseter afferents that bind isolectin B4 (IB4) are rare (5%; Ambalavanar et al 2003). In TG, TRPV1 is predominantly expressed in peptidergic afferents (Joseph et al 2019), and approximately 25% of masseter afferents express TRPV1 (Ro et al 2009). Recent studies have offered convincing evidence for the TRPV1 contribution to craniofacial muscle pain.…”

Section: Glutamate Receptor and Trp Channel Mechanisms In Peptidergicmentioning

confidence: 99%

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Neural Pathways of Craniofacial Muscle Pain: Implications for Novel Treatments

et al. 2020

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Craniofacial muscle pain is highly prevalent in temporomandibular disorders but is difficult to treat. Enhanced understanding of neurobiology unique to craniofacial muscle pain should lead to the development of novel mechanism-based treatments. Herein, we review recent studies to summarize neural pathways of craniofacial muscle pain. Nociceptive afferents in craniofacial muscles are predominantly peptidergic afferents enriched with TRPV1. Signals from peripheral glutamate receptors converge onto TRPV1, leading to mechanical hyperalgesia. Further studies are needed to clarify whether hyperalgesic priming in nonpeptidergic afferents or repeated acid injections also affect craniofacial muscle pain. Within trigeminal ganglia, afferents innervating craniofacial muscles interact with surrounding satellite glia, which enhances the sensitivity of the inflamed neurons as well as nearby uninjured afferents, resulting in hyperalgesia and ectopic pain originating from adjacent orofacial tissues. Craniofacial muscle afferents project to a wide area within the trigeminal nucleus complex, and central sensitization of medullary dorsal horn neurons is a critical factor in muscle hyperalgesia related to ectopic pain and emotional stress. Second-order neurons project rostrally to pathways associated with affective pain, such as parabrachial nucleus and medial thalamic nucleus, as well as sensory-discriminative pain, such as ventral posteromedial thalamic nuclei. Abnormal endogenous pain modulation can also contribute to chronic muscle pain. Descending serotonergic circuits from the rostral ventromedial medulla facilitate activation of second-order neurons in the trigeminal nucleus complex, which leads to the maintenance of mechanical hyperalgesia of inflamed masseter muscle. Patients with temporomandibular disorders exhibit altered brain networks in widespread cortical and subcortical regions. Recent development of methods for neural circuit manipulation allows silencing of specific hyperactive neural circuits. Chemogenetic silencing of TRPV1-expressing afferents or rostral ventromedial medulla neurons attenuates hyperalgesia during masseter inflammation. It is likely, therefore, that further delineation of neural circuits mediating craniofacial muscle hyperalgesia potentially enhances treatment of chronic muscle pain conditions.

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Section: Primary Afferents For Acute and Chronic Craniofacial Muscle mentioning

confidence: 99%

Section: Glutamate Receptor and Trp Channel Mechanisms In Peptidergicmentioning

confidence: 99%

Neural Pathways of Craniofacial Muscle Pain: Implications for Novel Treatments

et al. 2020

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“…The higher activities of corneal cold-sensitive nerves in previous reports would be maintained by endogenous TRPV1 ligands generated by ocular inflammation since perfusion of the TRPV1 antagonist in the present study had no significant effect on ongoing activities in cold-sensitive nerves (data not shown). Joseph et al (2019) reported that the phosphorylation of TRPV1 at S801 sensitizes the TRPV1-mediated current response in sensory neurons and potentiates pain behavior, which is involved in the generation of spontaneous pain in masseter inflammation. Therefore, TRPV1 phosphorylation may contribute to the sensitization of the TRPV1-mediated response under chronic tear deficiency in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…Joseph et al ( 2019 ) reported that the phosphorylation of TRPV1 at S801 sensitizes the TRPV1-mediated current response in sensory neurons and potentiates pain behavior, which is involved in the generation of spontaneous pain in masseter inflammation. Therefore, TRPV1 phosphorylation may contribute to the sensitization of the TRPV1-mediated response under chronic tear deficiency in the current study.…”

Section: Discussionmentioning

confidence: 99%

Chronic Tear Deficiency Sensitizes Transient Receptor Potential Vanilloid 1-Mediated Responses in Corneal Sensory Nerves

Masuoka

Yamashita

Nakano

et al. 2020

Front. Cell. Neurosci.

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Chronic tear deficiency enhances the excitability of corneal cold-sensitive nerves that detect ocular dryness, which can lead to discomfort in patients with dry eye disease (DED). However, changes in corneal nerve excitations through the polymodal nociceptor “transient receptor potential vanilloid 1” (TRPV1) and the potential link between this receptor and symptoms of DED remain unclear. In this study, we examined the firing properties of corneal cold-sensitive nerves expressing TRPV1 and possible contributions of chronic tear deficiency to corneal nerve excitability by TRPV1 activation. The bilateral excision of lacrimal glands in guinea pigs decreased the tear volume and increased the frequency of spontaneous eyeblinks 1–4 weeks after surgery. An analysis of the firing properties of the cold-sensitive nerves was performed by single-unit recordings of corneal preparations 4 weeks after surgery in both the sham-operated and gland-excised groups. Perfusion of the TRPV1 agonist, capsaicin (1 μM), transiently increased the firing frequency in approximately 46–48% of the cold-sensitive nerves characterized by low-background activity and high threshold (LB-HT) cold thermoreceptors in both groups. Gland excision significantly decreased the latency of capsaicin-induced firing in cold-sensitive nerves; however, its magnitude was unchanged. Calcium imaging of cultured trigeminal ganglion neurons from both groups showed that intracellular calcium elevation of corneal neurons induced by a low concentration of capsaicin (0.03 μM) was significantly larger in the gland excision group, regardless of responsiveness to cold. An immunohistochemical study of the trigeminal ganglion revealed that gland excision significantly increased the proportion of corneal neurons enclosed by glial fibrillary acidic protein (GFAP)-immunopositive satellite glial cells. Topical application of the TRPV1 antagonist, A784168 (30 μM), on the ocular surface attenuated eye-blink frequency after gland excision. Furthermore, gland excision enhanced blink behavior induced by a low concentration of capsaicin (0.1 μM). These results suggest that chronic tear deficiency sensitizes the TRPV1-mediated response in the corneal LB-HT cold thermoreceptors and cold-insensitive polymodal nociceptors, which may be linked to dry eye discomfort and hyperalgesia resulting from nociceptive stimuli in aqueous-deficient dry eyes.

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“…Masseter injection of TRPV1 antagonist further decreases spontaneous pain in both knock-in and wild-type (WT) genotypes, and the extent of inhibition is greater in WT than knock-in, suggesting that CFA-induced spontaneous pain is mediated by TRPV1 S801 phosphorylationdependent and independent mechanisms. 89 Masseter hyperalgesia induced by CFA or the injection of NMDA is also attenuated by TRPA1 inhibitor, suggesting interaction of NMDA receptor and TRPA1 in masseter afferents. 63 Although mechanisms underlying glutamate receptor and TRPA1 are not known, and need to be determined, it is noteworthy that TRPA1 phosphorylation also contributes to nociception.…”

Section: Activation Of Glutamate Receptors Regulates Trp Channel Signmentioning

confidence: 94%

Peripheral glutamate receptor and transient receptor potential channel mechanisms of craniofacial muscle pain

Chung

2020

Mol Pain

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Temporomandibular joint disorder is a common chronic craniofacial pain condition, often involving persistent, widespread craniofacial muscle pain. Although the etiology of chronic muscle pain is not well known, sufficient clinical and preclinical information supports a contribution of trigeminal nociceptors to craniofacial muscle pain processing under various experimental and pathological conditions. Here, we review cellular and molecular mechanisms underlying sensitization of muscle nociceptive afferents. In particular, we summarize findings on pronociceptive roles of peripheral glutamate in humans, and we discuss mechanistic contributions of glutamate receptors, including N-methyl-D-aspartate receptors and metabotropic glutamate receptors, which have considerably increased our understanding of peripheral mechanisms of craniofacial muscle pain. Several members of the transient receptor potential (TRP) family, such as transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1, also play essential roles in the development of spontaneous pain and mechanical hypersensitivity in craniofacial muscles. Furthermore, glutamate receptors and TRP channels functionally and bi-directionally interact to modulate trigeminal nociceptors. Activation of glutamate receptors invokes protein kinase C, which leads to the phosphorylation of TRPV1. Sensitization of TRPV1 by inflammatory mediators and glutamate receptors in combination with endogenous ligands contributes to masseter hyperalgesia. The distinct intracellular signaling pathways through which both receptor systems engage and specific molecular regions of TRPV1 are offered as novel targets for the development of mechanism-based treatment strategies for myogenous craniofacial pain conditions.

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Phosphorylation of TRPV1 S801 Contributes to Modality-Specific Hyperalgesia in Mice

Cited by 53 publications

References 44 publications

Neural Pathways of Craniofacial Muscle Pain: Implications for Novel Treatments

Neural Pathways of Craniofacial Muscle Pain: Implications for Novel Treatments

Chronic Tear Deficiency Sensitizes Transient Receptor Potential Vanilloid 1-Mediated Responses in Corneal Sensory Nerves

Peripheral glutamate receptor and transient receptor potential channel mechanisms of craniofacial muscle pain

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