The journal of pain : official journal of the American Pain Society
-
Voltage-gated Ca(2+) channels play an important role in nociceptive transmission. There is significant evidence supporting a role for N-, T- and P/Q-type Ca(2+) channels in chronic pain. Here, we report that A-1264087, a structurally novel state-dependent blocker, inhibits each of these human Ca(2+) channels with similar potency (IC50 = 1-2 μM). A-1264087 was also shown to inhibit the release of the pronociceptive calcitonin gene-related peptide from rat dorsal root ganglion neurons. Oral administration of A-1264087 produces robust antinociceptive efficacy in monoiodoacetate-induced osteoarthritic, complete Freund adjuvant-induced inflammatory, and chronic constrictive injury of sciatic nerve-induced, neuropathic pain models with ED50 values of 3.0, 5.7, and 7.8 mg/kg (95% confidence interval = 2.2-3.5, 3.7-10, and 5.5-12.8 mg/kg), respectively. Further analysis revealed that A-1264087 also suppressed nociceptive-induced p38 and extracellular signal-regulated kinase 1/2 phosphorylation, which are biochemical markers of engagement of pain circuitry in chronic pain states. Additionally, A-1264087 inhibited both spontaneous and evoked neuronal activity in the spinal cord dorsal horn in complete Freund adjuvant-inflamed rats, providing a neurophysiological basis for the observed antihyperalgesia. A-1264087 produced no alteration of body temperature or motor coordination and no learning impairment at therapeutic plasma concentrations. ⋯ The present results demonstrate that the neuronal Ca(2+) channel blocker A-1264087 exhibits broad-spectrum efficacy through engagement of nociceptive signaling pathways in preclinical pain models in the absence of effects on psychomotor and cognitive function.
-
Acupuncture-induced analgesia depends on the activation of endogenous pain modulation pathways. In this study, we asked whether ascending nociceptive control (ANC), a form of pain-induced analgesia, contributes to the antinociceptive effect of acupuncture. To answer this question, we tested the ability of procedures that block ANC-induced analgesia, at peripheral, spinal, nucleus accumbens and rostral ventral medulla levels, to block acupuncture-induced analgesia. Acupuncture at ST36 (Zusanli), a widely used acupoint located in the hind limb, induced potent heterosegmental antinociception in the orofacial formalin test. The magnitude of this antinociceptive effect was similar to that induced by an intraplantar injection of capsaicin, a procedure classically used to activate ANC. The antinociceptive effect of acupuncture was blocked by sciatic C-fibers depletion (1% perineural capsaicin), spinal administration of a μ-opioid (Cys2,Tyr3,Orn5,Pen7amide, .2 μg) or of a GABAA (bicuculline, .3 μg) receptor antagonist, intra-nucleus accumbens administration of a μ-opioid receptor antagonist (Cys2,Tyr3,Orn5,Pen7amide, 1 μg), or intrarostral ventral medulla administration of a nicotinic acetylcholine receptor antagonist (mecamylamine, .6 μg). In addition, acupuncture at ST36 and/or upper lip formalin induced c-Fos expression in the nucleus accumbens and in rostral ventral medulla. On the basis of these results, we propose that ANC contributes to the antinociceptive effect of acupuncture. ⋯ This article presents a novel mechanism of acupuncture analgesia, contributing to the understanding of its scientific basis. Because ANC is a pain modulation pathway activated by peripheral noxious stimulation that ascends to supraspinal regions, it could be the link between acupoint stimulation and the central mechanisms underlying acupuncture analgesia.