Abstract:The mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway plays a key role in mediating estrogen actions in the brain and neuronal sensitization during inflammation. Estrogen status is a risk factor in chronic temporomandibular muscle/joint disorders (TMJD); however, the basis for this relationship is not known. The present study tested the hypothesis that estrogen status acts through the MAPK/ERK signaling pathway to alter TMJ nociceptive processing. Single TMJ-responsive neurons … Show more
“…E2 increased masseter muscle inflammation-induced pERK in trigeminal ganglion cells exacerbating hyperalgesia and allodynia, and a MAPK inhibitor attenuated spinomedullary dorsal horn neuronal activity evoked by ATP in the normal and inflamed TMJ [49,75]. Significantly more ERK2 phosphorylation was detected in the hippocampus of E2-treated rats than OVx rats [9].…”
We previously reported that 17β -estradiol (E2) is pronociceptive in a visceral pain model in the rat. Subcutaneously (s.c.) administered E2 reversed the decrease in the colorectal distention (CRD)-evoked visceromotor response produced by ovariectomy (OVx) and CRD-induced nociceptive responses were greater in proestrous rats compared to met/diestrous rats. The site of action, the type of estrogen receptors activated and the possible intracellular signaling pathway involved are yet to be established. In the present study, intrathecal (i.t.) E2 administered to OVx rats mimicked the effects of s.c. E2, suggesting spinal E2 receptors are involved. This is further supported by the observations that the anti-estrogen ICI 182,780 injected i.t. in intact female rats significantly decreased the visceromotor response to CRD, the response of colonic afferents was not affected by OVx and colonic afferents did not label for estrogen receptor α (ERα). The ERα selective agonist, 4,4',4"-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol (PPT; s.c. or i.t.) facilitated the visceromotor response similar to E2, suggesting ERα activation is involved in mediating the pronociceptive effect of E2. PPT (s.c. or i.t.) increased the response of spinal dorsal horn neurons to CRD, indicating a spinal site of action. In addition, s.c. E2 or PPT increased CRD-induced spinal extracellular-signal-regulated kinase (ERK) phosphorylation that was not observed in OVx rats and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor blocked facilitation of the visceromotor response by PPT. Taken together, the present study demonstrates that spinal ERα mediates the pronociceptive effect of E2 on visceral signal processing through activation of the MAPK pathway.
“…E2 increased masseter muscle inflammation-induced pERK in trigeminal ganglion cells exacerbating hyperalgesia and allodynia, and a MAPK inhibitor attenuated spinomedullary dorsal horn neuronal activity evoked by ATP in the normal and inflamed TMJ [49,75]. Significantly more ERK2 phosphorylation was detected in the hippocampus of E2-treated rats than OVx rats [9].…”
We previously reported that 17β -estradiol (E2) is pronociceptive in a visceral pain model in the rat. Subcutaneously (s.c.) administered E2 reversed the decrease in the colorectal distention (CRD)-evoked visceromotor response produced by ovariectomy (OVx) and CRD-induced nociceptive responses were greater in proestrous rats compared to met/diestrous rats. The site of action, the type of estrogen receptors activated and the possible intracellular signaling pathway involved are yet to be established. In the present study, intrathecal (i.t.) E2 administered to OVx rats mimicked the effects of s.c. E2, suggesting spinal E2 receptors are involved. This is further supported by the observations that the anti-estrogen ICI 182,780 injected i.t. in intact female rats significantly decreased the visceromotor response to CRD, the response of colonic afferents was not affected by OVx and colonic afferents did not label for estrogen receptor α (ERα). The ERα selective agonist, 4,4',4"-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol (PPT; s.c. or i.t.) facilitated the visceromotor response similar to E2, suggesting ERα activation is involved in mediating the pronociceptive effect of E2. PPT (s.c. or i.t.) increased the response of spinal dorsal horn neurons to CRD, indicating a spinal site of action. In addition, s.c. E2 or PPT increased CRD-induced spinal extracellular-signal-regulated kinase (ERK) phosphorylation that was not observed in OVx rats and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor blocked facilitation of the visceromotor response by PPT. Taken together, the present study demonstrates that spinal ERα mediates the pronociceptive effect of E2 on visceral signal processing through activation of the MAPK pathway.
“…Local injection of CFA (Shinoda et al, 2005;Tashiro et al, 2009), capsaicin (Honda et al, 2008), carrageenan (Teixeira et al, 2010), or formalin (Wu et al, 2009) induces local inflammation in the trigeminal region and results in pain-related behavior, including mechanical and heat hypersensitivity at the inflamed site. However, these models assessed changes in mechanical or heat sensitivity at the inflamed site; few models inducing ectopic inflammatory pain in the noninflamed adjacent division of the trigeminal nerve have been developed in the orofacial region.…”
Section: Model Of Ectopic Trigeminal Inflammatory Painmentioning
It is well known that oral inflammation causes tenderness in temporomandibular joints or masseter muscles. The exact mechanism of such an orofacial ectopic hyperalgesia remains unclear. Here, we investigated the functional significance of interaction of nerve growth factor (NGF) and transient receptor potential vanilloid 1 (TRPV1) in relation to heat hyperalgesia in the whisker pad skin caused by complete Freund's adjuvant (CFA) injection into the lower lip. CFA injection induced heat hyperalgesia of the ipsilateral whisker pad skin. Moreover, it leads to enhancement of spontaneous activity and heat responses in trigeminal ganglion (TG) neurons that was elicited by heat stimulation of the whisker pad skin. The heat hyperalgesia was dose-dependently reversed by intraperitoneal TRPV1 antagonist administration, also diminished by neutralizing anti-NGF antibody administration into the lower lip and intraganglionic administration of K252a, a tyrosine kinase receptor inhibitor. Nerve fibers in bundle of mandibular nerve and TG neurons that innervates the whisker pad skin and lower lip both expressed labeled NGF, which was administrated into the lower lip. Moreover, the NGF concentrations in ophthalmic-maxillary and mandibular divisions of the TG increased after CFA injection into the lower lip. The number of TRPV1-positive neurons that innervates the whisker pad skin and lower lip was increased after CFA injection into the lower lip, and this increase was annulled by anti-NGF administration. The present findings suggest that inflammation in the lower lip induces release of NGF that regulates TRPV1 expression in TG neurons. This TRPV1 overexpression may underlie ectopic heat hyperalgesia in the whisker pad skin.
“…Previously we determined that the response properties of TMJ neurons in superficial laminae varied significantly over different stages of the estrous cycle in intact female rats (Okamoto et al 2003), while exogenous E2 treatment increased the TMJ-evoked responses of neurons in superficial but not in deeper laminae in ovariectomized female rats (Tashiro et al 2007; Okamoto et al 2013). Although estrogen status markedly affected the response of TMJ-responsive neurons to NMDA receptor antagonism (Tashiro et al, 2009a) and inhibition of MAP kinase activity consistent with central sensitization (Tashiro et al, 2009b), little is known about estrogen status, disinhibition and GABAergic function in TMJ nociception. GABAergic neurons are found throughout the trigeminal brainstem sensory complex and are densely distributed in superficial laminae of Vc (Ginestal and Matute, 1993; Polgar and Antal, 1995; Avendano et al, 2005).…”
Sensory input from the temporomandibular joint (TMJ) to neurons in superficial laminae at the spinomedullary (Vc/C1–2) region is strongly influenced by estrogen status. This study determined if GABAergic mechanisms play a role in estrogen modulation of TMJ nociceptive processing in ovariectomized female rats treated with high (HE) or low dose (LE) estradiol (E2) for two days. Superficial laminae neurons were activated by ATP (1 mM) injections into the joint space. The selective GABAA receptor antagonist, bicuculline methiodide (BMI, 5 or 50 μM, 30 μl), applied at the site of recording greatly enhanced the magnitude and duration of ATP-evoked responses in LE rats, but not in units from HE rats. The convergent cutaneous receptive field (RF) area of TMJ neurons was enlarged after BMI in LE but not HE rats, while resting discharge rates were increased after BMI independent of estrogen status. By contrast, the selective GABAA receptor agonist, muscimol (50 μM, 30 μl), significantly reduced the magnitude and duration of ATP-evoked activity, resting discharge rate, and cutaneous RF area of TMJ neurons in LE and HE rats, whereas lower doses (5 μM) affected only units from LE rats. Protein levels of GABAA receptor β3 isoform at the Vc/C1–2 region were similar for HE and LE rats. These results suggest that GABAergic mechanisms contribute significantly to background discharge rates and TMJ-evoked input to superficial laminae neurons at the Vc/C1–2 region. Estrogen status may gate the magnitude of GABAergic influence on TMJ neurons at the earliest stages of nociceptive processing at the spinomedullary region.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.