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.

[1] Recognizing that the flow dimension n in the generalized radial flow (GRF) model [Barker, 1988] may reflect hydrogeologic boundaries, aquitard leakage, or aquifer heterogeneity in hydraulic tests, Walker and Roberts [2003] determined the (apparent) flow dimensions of a few idealized systems with such hydrogeologic features. Their method starts with the determination of the large-time asymptotic value of the pressure derivative of drawdown variation h (r, t), n, usingWalker and Roberts correctly calculated n of the drawdown solutions appropriate for the idealized systems. However, the subsequent determination of the apparent flow dimensions using the following equation is subject to debate[3] This is because the interconnection between equations (1) and (2) is associated with the generalized drawdown solution to the GRF model for constant rate pumping using a line sink [Barker, 1988, equation (32)], namely,where Q is the constant pumping rate, K the constant hydraulic conductivity, r the apparent radial distance as the product of the linear (Euclidean) distance and tortuosity, b the extent of the flow regime, G(Àn, n) the complementary incomplete Gamma function, and u = r 2