Ca_v3.2 T-Type Ca²⁺Channel-Dependent Activation of ERK in Paraventricular Thalamus Modulates Acid-Induced Chronic Muscle Pain

Abstract

Treatments for chronic musculoskeletal pain, such as lower back pain, fibromyalgia, and myofascial pain syndrome, remain inadequate because of our poor understanding of the mechanisms that underlie these conditions. Although T-type Ca 2ϩ channels (T-channels) have been implicated in peripheral and central pain sensory pathways, their role in chronic musculoskeletal pain is still unclear. Here, we show that acid-induced chronic mechanical hyperalgesia develops in Ca v 3.1-deficient and wild-type but not in Ca v 3.2-deficient male and female mice. We also show that T-channels are required for the initiation, but not maintenance, of acid-induced chronic muscle pain. Blocking T-channels using ethosuximide prevented chronic mechanical hyperalgesia in wild-type mice when administered intraperitoneally or intracerebroventricularly, but not intramuscularly or intrathecally. Furthermore, we found an acid-induced, Ca v 3.2 T-channeldependent activation of ERK (extracellular signal-regulated kinase) in the anterior nucleus of paraventricular thalamus (PVA), and prevention of the ERK activation abolished the chronic mechanical hyperalgesia. Our findings suggest that Ca v 3.2 T-channel-dependent activation of ERK in PVA is required for the development of acid-induced chronic mechanical hyperalgesia.

Role of Extracellular Signal-Regulated Kinase in Synaptic Transmission and Plasticity of a Nociceptive Input on Capsular Central Amygdaloid Neurons in Normal and Acid-Induced Muscle Pain Mice

“…The scale bar in B1a is 500 m and also applies to B1b and B2a and B2b, while that in B2c is 50 m and also applies to (2001), which is generally accepted as an animal model for chronic musculoskeletal pain syndrome, such as fibromyalgia, arthritis, and myofacial pain syndromes. Consistent with the results of a study by Sluka et al (2001) (see also Chen et al, 2010), injection of acidic saline into the left gastrocnemius muscle induced transient mechanical hypersensitivity, and a second dose of acidic saline given 3 d later produced a long-lasting mechanical hypersensitivity in both hindpaws (n ϭ 6 animals) (Fig. 5A, triangles).…”

“…Since increased pERK levels in the CeAC result in behavioral hypersensitivity in mice (Carrasquillo and Gereau, 2007;Chen et al, 2010), we compared the effects of ERK activation on the mean incidence and amplitude of PBA-CeAC aEPSCs in slices from AIMP mice and controls. We adopted the AIMP model developed by Sluka et al .…”

“…They also showed that direct injection into the CeAC of an ERK activator [phorbol 12,13-diacetate (PDA)] or blocker (U0126) respectively increases or reduces behavioral hypersensitivity in normal animals or those with formalin-induced pain. Recently, Chen et al (2010) also showed increased levels of pERK in the central nucleus of the amygdala in the acid-induced muscle pain (AIMP). These studies suggest that ERK activation in the CeAC is directly involved in central sensitization.…”

“…In neuropathic and arthritic pain models, synaptic transmission of the PBA pathway on CeAC neurons (referred as to PBA-CeAC synapses) is enhanced (Neugebauer et al, 2003;Ikeda et al, 2007). However, whether such a change in efficacy of PBA-CeAC synapses is related to the reported elevation of ERK activity in the CeAC in animals with behavioral hypersensitivity (Carrasquillo and Gereau, 2007;Chen et al, 2010) remains unclear. We addressed this issue by examining the effect of an ERK activator, PDA, on the function of PBA-CeAC synapses and the interactions of ERK activation and LTP expression at these synapses in slices from normal mice and mice subjected to AIMP.…”

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

“…T-type Ca 2+ channels are highly expressed in many developing tissues and are implicated in regulating cellular events leading to cell proliferation and differentiation (50). Calcium influx through T-type Ca 2+ channels activates several cellular pathways, including calcineurin/NFAT (29,39), extracellular signal-regulated kinase (31,(51)(52)(53), nitric oxide synthase 3 (54), and Ca 2+ /calmodulindependent protein kinase II (55). However, the detailed mechanisms linking these T-type Ca 2+ channel-activated signaling pathways to cell proliferation and differentiation are not completely clear.…”