Articles: neuralgia.
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We have recently shown that spinal sigma-1 receptor (Sig-1R) activation facilitates nociception via an increase in phosphorylation of the N-methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). The present study was designed to examine whether the Sig-1R-induced facilitative effect on NMDA-induced nociception is mediated by D-serine, and whether D-serine modulates spinal pGluN1 expression and the development of neuropathic pain after chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the D-serine degrading enzyme, D-amino acid oxidase attenuated the facilitation of NMDA-induced nociception induced by the Sig-1R agonist, 2-(4-morpholinethyl)1-phenylcyclohexane carboxylate. Exogenous D-serine increased protein kinase C (PKC)-dependent (Ser896) pGluN1 expression and facilitated NMDA-induced nociception, which was attenuated by preteatment with the PKC inhibitor, chelerythrine. In CCI mice, administration of the serine racemase inhibitor, L-serine O-sulfate potassium salt or D-amino acid oxidase on postoperative days 0 to 3 suppressed CCI-induced mechanical allodynia (MA) and pGluN1 expression on day 3 after CCI surgery. Intrathecal administration of D-serine restored MA as well as the GluN1 phosphorylation on day 3 after surgery that was suppressed by the Sig-1R antagonist, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide or the astrocyte inhibitor, fluorocitrate. In contrast, D-serine had no effect on CCI-induced thermal hyperalgesia or GluN1 expression. These results indicate that spinal D-serine: 1) mediates the facilitative effect of Sig-1R on NMDA-induced nociception, 2) modulates PKC-dependent pGluN1 expression, and 3) ultimately contributes to the induction of MA after peripheral nerve injury. ⋯ This report shows that reducing D-serine suppresses central sensitization and significantly alleviates peripheral nerve injury-induced chronic neuropathic pain and that this process is modulated by spinal Sig-1Rs. This preclinical evidence provides a strong rationale for using D-serine antagonists to treat peripheral nerve injury-induced neuropathy.
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MyD88 is the adaptor protein of MyD88-dependent signaling pathway of TLRs and IL-1 receptor and regulates innate immune response. However, it was not clear whether and how MyD88 and related signaling pathways in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) are involved in neuropathic pain. ⋯ MyD88-dependent TIR pathway in the DRG and SDH may play a role in CCI-induced neuropathic pain. MyD88 might serve as a potential therapeutic target for neuropathic pain.
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Randomized Controlled Trial
Ipsilateral and contralateral sensory changes in healthy subjects after experimentally induced concomitant sensitization and hypoesthesia.
In unilateral neuropathic pain. e.g. after peripheral nerve injury, both positive and negative sensory signs occur often, accompanied by minor but equally directed contralateral sensory changes. To mimic this feature, we experimentally aimed to induce concomitant c-fibre sensitization and block in healthy subjects and analyzed the bilateral sensory changes by quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain. ⋯ The present experimental model using combined application of capsaicin and LA imitates partly the complex sensory changes observed in patients with unilateral neuropathic pain and might be used as an additional surrogate model. Only the concomitant use both agents in the same area induces both positive and negative sensory signs ipsilaterally as well as parallel contralateral sensory changes (to a lesser extent).
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Patients with multiple sclerosis (MS) often complain of neuropathic pain. According to the Gate Control Theory of Pain, spinal networks of GABAergic inhibitory interneurons are important in modulating nociceptive inputs from the periphery. Na+-K+-2Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) generally dictate the tone of GABA/glycine inhibition by regulating intracellular chloride concentrations. ⋯ Treatment with bumetanide, an NKCC inhibitor, had no effect on mechanical hypersensitivity seen in mice with EAE even though it reversed the changes in the levels of NKCC1 and KCC2. We noted that bumetanide treatment, while effective at reversing the changes in monomeric KCC2 levels was ineffective at reversing the changes in oligomeric KCC2 which remained repressed. These results indicate that mechanical hypersensitivity in EAE is not mediated by altered levels of NKCC1.
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Several drugs and agents are currently used for the treatment of neuropathic pain. Among them amitriptyline, a tricyclic antidepressant drug, represent a first line treatment. Despite its well-documented clinical efficacy, amitriptyline is ineffective in some animal models of neuropathic pain. ⋯ Additionally, amitriptyline further promoted astrocyte activation in neuropathic mice, as illustrated by the increased expression of glial fibrillary acidic protein (GFAP), that was attenuated by intrathecal injection of the JNK inhibitor. These data indicate astrocyte JNK activation as counteracting pathway to amitriptyline analgesic response. Targeting the JNK pathway in spinal astroglia may present an efficient way to improve the analgesic efficacy of amitriptyline in the neuropathic pain treatment.