Article

Functional interactions between NMDA receptors and TRPV1 in trigeminal sensory neurons mediate mechanical hyperalgesia in the rat masseter muscle

University of Maryland School of Dentistry, Department of Neural and Pain Sciences, Program in Neuroscience, Baltimore, MD 21201, USA.
Pain (Impact Factor: 5.21). 05/2012; 153(7):1514-24. DOI: 10.1016/j.pain.2012.04.015
Source: PubMed

ABSTRACT

The NMDA and TRPV1 receptors that are expressed in sensory neurons have been independently demonstrated to play important roles in peripheral pain mechanisms. In the present study, we investigated whether the 2 receptor-channel systems form a functional complex that provides the basis for the development of mechanical hyperalgesia. In the masseter muscle, direct application of NMDA induced a time-dependent increase in mechanical sensitivity, which was significantly blocked when the muscle was pretreated with a specific TRPV1 antagonist, AMG9810. The NR1 subunit of the NMDA receptor and TRPV1 were coexpressed in 32% of masseter afferents in trigeminal ganglia (TG). Furthermore, NR1 and NR2B formed protein-protein complexes with TRPV1 in TG as demonstrated by coimmunoprecipitation experiments. Calcium imaging analyses further corroborated that NMDA and TRPV1 receptors functionally interact. In TG culture, application of NMDA resulted in phosphorylation of serine, but not threonine or tyrosine, residues of TRPV1 in a time course similar to that of the development of NMDA-induced mechanical hyperalgesia. The NMDA-induced phosphorylation was significantly attenuated by CaMKII and PKC inhibitors, but not by a PKA inhibitor. Consistent with the biochemical data, the NMDA-induced mechanical hyperalgesia was also effectively blocked when the muscle was pretreated with a CaMKII or PKC inhibitor. Thus, NMDA receptors and TRPV1 functionally interact via CaMKII and PKC signaling cascades and contribute to mechanical hyperalgesia. These data offer novel mechanisms by which 2 ligand-gated channels in sensory neurons interact and reinforce the notion that TRPV1 functions as a signal integrator under pathological conditions.

Download full-text

Full-text

Available from: Jin Y Ro, Jun 16, 2015
  • Source
    • "both TRPV1 and TRPA1. ATP or glutamate-induced mechanical hypersensitivity is prevented when either PKC or CaMKII is inhibited, and the inhibition of TRPV1 similarly suppressed the muscular hypersensitivity (Lee et al., 2012b; Saloman et al., 2013). Both P2X 3 and NMDAR activation induces phosphorylation of TRPV1, including serine 800 site, which is the major underlying mechanism for TRPV1 sensitization (Lee et al., 2012a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: TRPA1 is expressed in muscle afferents and direct activation of these receptors induces acute mechanical hypersensitivity. However, the functional role of TRPA1 under pathological muscle pain conditions and mechanisms by which TRPA1 mediate muscle pain and hyperalgesia are not clearly understood. Two rodent behavioral models validated to assess craniofacial muscle pain conditions were used to study ATP- and NMDA-induced acute mechanical hypersensitivity and complete Freund's adjuvant (CFA)-induced persistent mechanical hypersensitivity. The rat grimace scale was utilized to assess inflammation-induced spontaneous muscle pain. Behavioral pharmacology experiments were performed to assess the effects of AP18, a selective TRPA1 antagonist under these conditions. TRPA1 expression levels in trigeminal ganglia were examined before and after CFA treatment in the rat masseter muscle. Pre-treatment of the muscle with AP18 dose-dependently blocked the development of acute mechanical hypersensitivity induced by NMDA and αβmeATP, a specific agonist for NMDA and P2X3 receptor, respectively. CFA-induced mechanical hypersensitivity and spontaneous muscle pain responses were significantly reversed by post-treatment of the muscle with AP18 when CFA effects were most prominent. CFA-induced myositis was accompanied by significant up-regulation of TRPA1 expression in TG. Our findings showed that TRPA1 in muscle afferents plays an important role in the development of acute mechanical hypersensitivity and in the maintenance of persistent muscle pain and hypersensitivity. Our data suggested that TRPA1 may serve as a downstream target of pro-nociceptive ion channels, such as P2X3 and NMDA receptors in masseter afferents, and that increased TRPA1 expression under inflammatory conditions may contribute to the maintenance of persistent muscle pain and mechanical hyperalgesisa. Mechanistic studies elucidating transcriptional or post-translational regulation of TRPA1 expression under pathological pain conditions should provide important basic information to further advance the treatment of craniofacial muscle pain conditions.
    Full-text · Article · Sep 2015 · Neuroscience
  • Source
    • "Intramuscular injection of high-temperature saline causes mild muscle pain in healthy humans (Graven-Nielsen et al., 2002). The transient receptor potential vanilloid 1 (TRPV1) channel, which responds to noxious heat (>42 °C), protons and capsaicin , is expressed by masseter muscle nociceptors and may mediate muscle pain following activation by temperatures of 48 °C or more (Connor et al., 2005; Szallasi et al., 2006; Levine and Alessandri- Haber, 2007; Ro et al., 2009; Lee et al., 2012a,b;). Other evidence has concluded that TRPV1 receptor activation contributes to nociception when tissue pH becomes very acidic (pH ≤6.0) (Ugawa et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study was conducted to determine whether glutamate-evoked jaw muscle pain is modulated by the acidity and temperature of the solution injected. Thirty two participants participated and received injections of high-temperature acidic (HT-A) glutamate (pH 4.8, 48 °C), high-temperature neutral (HT-N) glutamate (pH 7.0, 48 °C) and neutral temperature neutral (NT-N) glutamate (pH 7.0, 38 °C) solutions (0.5 mL) into the masseter muscle. Pain intensity was assessed with an electronic visual analogue scale (eVAS). Numerical rating scale (NRS) scores of unpleasantness and temperature perception, pain-drawing areas, mechanical sensitivity and pressure pain thresholds (PPT) were also measured. Participants filled out the McGill Pain Questionnaire (MPQ). One or two way ANOVAs were used for data analyses. Injection of HT-A glutamate solutions significantly increased the area under the VAS-time curve compared with injection of HT-N glutamate and NT-N glutamate solution (p < 0.040). The duration of glutamate-evoked pain was significantly longer when HT-A glutamate was injected than when NT-N glutamate was injected (p < 0.017). No significant effects of acidity were detected on pain drawings, NRS unpleasantness and heat perception, but there was a significant effect of acidity on MPQ scores and mechanical sensitivity. Acidity and temperature modulate glutamate-evoked jaw muscle pain suggesting an interaction between acid sensing and glutamate receptors which could be of importance for understanding clinical muscle pain conditions. © 2015 European Pain Federation - EFIC®
    Full-text · Article · Mar 2015 · European journal of pain (London, England)
    • "In addition, potential patho(physio)logic consequences of permanently increased CaMKIIa activity in sensory neurons include: nociceptive hypersensitivity and mechanical hyperalgesia through a modulation of TRPV1 activity and its interaction with NMDA receptors (Price et al., 2005; Lee et al., 2012), or activation of purinergic P2X 3 receptors (Nair et al., 2010); as well as mediation of reactive oxygen species increase and cell damage (Kim et al., 2011; Nishio et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The activity of calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. The aim of this study was to investigate the immunoreactivity of phosphorylated CaMKIIα (pCaMKIIα) in subpopulations of trigeminal ganglion (TG) neurons in rat models of early diabetes type 1 (dm1) and 2 (dm2). DM1 model was induced with intraperitoneally (i.p.) injected streptozotocin (STZ) (55mg/kg). DM2 rats were fed with the high fat diet (HFD) for two weeks and then received 35mg/kg of STZ i.p. Two weeks and 2 months after the STZ-diabetes induction, rats were sacrificed and immunohistocemical analysis for detection of pCaMKIIα immunoreactivity and double immunoflorescence labeling with isolectin (IB4) was performed. Increased intensity of pCaMKIIα immunofluorescence, restricted to IB4-negative small-diameter neurons, was seen in TG neurons two months after STZ-DM1 induction. DM1 model, as well as the obesity (control dm2 groups) resulted in neuronal impaired growth while dm2 model led to neuron hypertrophy in TG. Observed changes may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. In future, innovative strategies for modulation of CaMKIIα activity in specific subpopulations of neurons could be a novel approach in therapy of diabetic trigeminal neuropathy. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Feb 2015 · Journal of Chemical Neuroanatomy
Show more