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Depletion of Foxp3+ regulatory T cells increases severity of mechanical allodynia and significantly alters systemic cytokine levels following peripheral nerve injury.

Neuropathic pain is a debilitating condition caused by damage to the somatosensory nervous system, such as peripheral nerve injury. The immune system, and in particular the adaptive T cell response, plays a key role in mediating such pain. Regulatory T (Treg) cells are a small subpopulation of inhibitory T cells that prevent autoimmunity, limit immunopathology and maintain immune homeostasis. Here, we investigated the effects of conditional depletion of Treg cells on mechanical allodynia and serum cytokines in mice with chronic constriction injury (CCI) of the sciatic nerve, an animal model of

Huwentoxin-XVI, an analgesic, highly reversible mammalian N-type calcium channel antagonist from Chinese tarantula Ornithoctonus huwena.

N-type calcium channels play important roles in the control of neurotransmission release and transmission of pain signals to the central nervous system. Their selective inhibitors are believed to be potential drugs for treating chronic pain. In this study, a novel neurotoxin named Huwentoxin-XVI (HWTX-XVI) specific for N-type calcium channels was purified and characterized from the venom of Chinese tarantula Ornithoctonus huwena. HWTX-XVI is composed of 39 amino acid residues including six cysteines that constitute three disulfide bridges. HWTX-XVI could almost completely block the twitch resp

Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling.

Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced b

The efficacy of morphine, pregabalin, gabapentin, and duloxetine on mechanical allodynia is different from that on neuroma pain in the rat neuropathic pain model.

BACKGROUND: It has been reported that <50% of neuropathic pain patients are satisfactorily treated with drugs. It is possible that this lack of efficacy of drugs on neuropathic pain might be due to the drugs prescribed, regardless of the origin of pain. We compared the efficacy of orally administered morphine, pregabalin, gabapentin, and duloxetine on mechanical allodynia with that on neuroma pain using the tibial neuroma transposition (TNT) model. METHODS: In the TNT model, the tibial nerve is transected, and the tibial nerve stump is transpositioned to the lateral aspect of the hindlimb. Af

Analgesic effect of iridoid glycosides from Paederia scandens (LOUR.) MERRILL (Rubiaceae) on spared nerve injury rat model of neuropathic pain.

Iridoid glycosides of Paederia scandens (IGPS) is a major active component isolated from traditional Chinese herb P. scandens (LOUR.) MERRILL (Rubiaceae). The aim of the present study was to investigate the analgesic effect of IGPS on spared nerve injury (SNI) model of neuropathic pain. The SNI model in rats was established by complete transection of the common peroneal and tibial distal branches of the sciatic nerve, leaving the sural branch intact. The mechanical withdrawal threshold (MWT) in response to mechanical stimulation was measured by electronic von Frey filaments on day 1 before ope

Simvastatin ameliorates cauda equina compression injury in a rat model of lumbar spinal stenosis.

Lumbar spinal stenosis (LSS) is the leading cause of morbidity and mortality worldwide. LSS pathology is associated with secondary injury caused by inflammation, oxidative damage and cell death. Apart from laminectomy, pharmacological therapy targeting secondary injury is limited. Statins are FDA-approved cholesterol-lowering drug. They also show pleiotropic anti-inflammatory, antioxidant and neuroprotective effects. To investigate the therapeutic efficacy of simvastatin in restoring normal locomotor function after cauda equina compression (CEC) in a rat model of LSS, CEC injury was induced in

The soy isoflavone genistein reverses oxidative and inflammatory state, neuropathic pain, neurotrophic and vasculature deficits in diabetes mouse model.

Treatment of diabetes complications remains a substantial challenge. The aim of this study was to explore the ability of the soy isoflavone genistein in attenuating the signs that follow diabetes onset: nociceptive hypersensitivity, oxidative and inflammatory state, nerve growth factor (NGF) decrease and vascular dysfunctions. Genistein (3 and 6 mg/kg) was administered to C57BL/6J streptozotocin diabetic mice from the 2nd till the 5th week after disease induction. The hind paw withdrawal threshold to mechanical stimulation (tactile allodynia) was evaluated by a von Frey filament. The oxidative

Trigeminal injury causes kappa opioid-dependent allodynic, glial and immune cell responses in mice.

BACKGROUND: The dynorphin-kappa opioid receptor (KOR) system regulates glial proliferation after sciatic nerve injury. Here, we investigated its role in cell proliferation following partial ligation of infraorbital nerve (pIONL), a model for trigeminal neuropathic pain. Mechanical allodynia was enhanced in KOR gene deleted mice (KOR-/-) compared to wild type mice. Using bromodeoxyuridine (BrdU) as a mitotic marker, we assessed cell proliferation in three different areas of the trigeminal afferent pathway: trigeminal nucleus principalis (Vp), trigeminal root entry zone (TREZ), and trigeminal ga

Functional and biochemical evidence indicating beneficial effect of Melatonin and Nicotinamide alone and in combination in experimental diabetic neuropathy.

Oxidative stress resulting in excessive generation of ROS is a compelling initiator of DNA damage along with damage to various cellular proteins and other macromolecules. Poly(ADP-ribose) polymerase (PARP) activation in response to DNA damage, stirs an energy-consuming cellular metabolic cycle; culminating into cell death. The present study was designed to determine the effect of combining an antioxidant, Melatonin and a PARP inhibitor, Nicotinamide on the hallmark deficits developing in diabetic neuropathy (DN). Streptozotocin (STZ, 55 mg/kg, i.p.) was administered to induce diabetes. Six wee

Antinociceptive effect of chronic lithium on visceral hypersensitivity in a rat model of diarrhea-predominant irritable bowel syndrome: The role of nitric oxide pathway.

BACKGROUND AND AIM: Lithium, a widely used drug in bipolar-affective disorders, plays gastro-protective roles. The effects of lithium on several tissues are mediated through nitric oxide (NO), which regulates gastrointestinal motility and mucosal integrity. The aim of this study was to investigate the protective effect of chronic lithium administration on visceral hypersensitivity and to investigate the role of NO as a potential mechanism of lithium in a rat model of irritable bowel syndrome. METHODS: Colitis was induced by the intracolonic administration of acetic acid. After subsidence of i

Spinal cord stimulation in sympathetically maintained complex regional pain syndrome type I with severe disability. A prospective clinical study.

BACKGROUND AND PURPOSE: In this prospective trial we assessed the long-term effect of spinal cord stimulation (SCS) on the improvement of functional status in complex regional pain syndrome type I (CRPS I). METHODS: A prerequisite for eligibility to SCS treatment was the responsiveness of patients to sympathetic nerve block. In 29 patients with chronic sympathetically maintained CRPS I, the efficacy of SCS on deep pain, allodynia and functional disability was determined. Pain intensity was estimated during SCS free intervals of 45 min (inactivation test) every 3 months and compared with that

[Esketamine Alleviates Postoperative Depressive Symptoms in Frail Elderly Patients Undergoing Thoracoscopic Radical Resection of Lung Cancer: A Randomized Double-Blind Controlled Trial].

OBJECTIVE: To investigate the effect of esketamine on postoperative depression in frail elderly patients undergoing thoracoscopic radical re … up was significantly reduced (P < 0.05 or 0.01); the incidence of postoperative nausea/vomiting and hyperalgesia was significantly lower (P < 0.01); the duration of postoperative mechanical ventilation, length-of-stay in postanesthesia care unit (PACU), and postoperative length-of-stay in the hospital were significantly shorter (P < 0.01). CONCLUSION: Esketam …

Opioids compared to placebo or other treatments for chronic low-back pain.

BACKGROUND: The use of opioids in the long-term management of chronic low-back pain (CLBP) has increased dramatically. Despite this trend, t … rious adverse effects, risks (addiction or overdose), or complications (sleep apnea, opioid-induced hyperalgesia, hypogonadism). In general, the effect sizes were medium for pain and small for function. AUTHORS' CONCLUSIONS: There is some evidence (very low to moderate quality) for short-term efficacy (for both pain and function) of opioids to treat CLBP comp …

Elucidation of pathophysiology and treatment of neuropathic pain.

Neuropathic pain, pain arising as a direct consequence of a lesion or disease affecting the somatosensory system, is relatively common, occurring in about 1% of the population. Studies in animal models describe a number of peripheral and central pathophysiological processes after nerve injury that would be the basis of underlying neuropathic pain mechanism. Additionally, neuro-imaging (positron emission tomography and functional magnetic resonance imaging) provides insights in brain mechanisms corresponding with mechanistic processes including allodynia, hyperalgesia, altered sensation, and sp…

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy; cause and effect?

AbstractCancer is the second leading cause of death worldwide and is a major global health burden. Significant improvements in survival have been achieved, due in part to advances in adjuvant antineoplastic chemotherapy. The most commonly used antineoplastics belong to the taxane, platinum, and vinca alkaloid families. While beneficial, these agents are frequently accompanied by severe side effects, including chemotherapy-induced peripheral neuropathy (CPIN). While CPIN affects both motor and sensory systems, the majority of symptoms are sensory, with pain, tingling, and numbness being the pre

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… /hyperalgesia 54 , 71 , 72 • α 2 δ inhibitor reduced mechanical allodynia and hyperalgesia 49 – 52 , 73 TRP channels • TRPA1 −/− or inhibitor inhibits mechanical and cold allodynia and heat hyperalgesia 74 , 75 • TRPV4 inhibitor inhibits mechanical allodynia and heat hyperalgesia 74 , 75 • TRPV1 antagonists … cold hyperalgesia/allodynia. …

IKK/NF-κB-dependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury.

Increasing evidence indicates that both microglia and satellite glial cell (SGC) activation play causal roles in neuropathic pain development after peripheral nerve injury; however, the activation mechanisms and their contribution to neuropathic pain remain elusive. To address this issue, we generated Ikkβ conditional knockout mice (Cnp-Cre/Ikkβ; cIkkβ) in which IKK/NF-κB-dependent proinflammatory SGC activation was abrogated. In these mice, nerve injury-induced spinal cord microglia activation and pain hypersensitivity were significantly attenuated compared to those in control mice. In additi

Acute sacral nerve stimulation reduces visceral mechanosensitivity in Rat through spinal opioid pathway.

BACKGROUND: Sacral nerve stimulation (SNS) is an alternative surgical treatment of refractory urge incontinence and/or fecal incontinence. Despite its clinical efficacy, the mechanisms of action of SNS remain poorly understood. The aim of this experimental study was to evaluate the effect of SNS on visceral mechanosensitivity in rats. METHODS: Anesthetized Sprague-Dawley rats were treated with SNS or sham stimulation. SNS was performed by implanting an electrode close to the sacral nerve root S1. Rats were administered either a non-selective opioid receptor antagonist (naloxone) or a nitric o

β2- and β3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines.

Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by both β2- and β3-adrenergic receptors (β2ARs and β3ARs). Here we investigated molecules downstream of β2- and β3ARs driving pain in animals with decreased COMT activity. Based on evidence linking their role in pain and synthesis downstream of β2- and β3AR stimulation, we hypothesized that nitric oxide (NO) and proinflammatory cytokines drive COMT-dependent pain. To test

Descending controls modulate inflammatory joint pain and regulate CXC chemokine and iNOS expression in the dorsal horn.

BACKGROUND: Descending control of nociceptive processing, by pathways originating in the rostral ventromedial medulla (RVM) and terminating in the dorsal horn, contributes to behavioural hypersensitivity in a number of pain models. Two facilitatory pathways have been identified and are characterized by serotonin (5-HT) content or expression of the mu opiate receptor. Here we investigated the contribution of these pathways to inflammatory joint pain behaviour and gene expression changes in the dorsal horn. RESULTS: Selective lesion of the descending serotonergic (5-HT) pathway by prior intrath

Lidocaine attenuates the development of diabetic-induced tactile allodynia by inhibiting microglial activation.

BACKGROUND: Lidocaine is used clinically for tactile allodynia associated with diabetes-induced neuropathy. Although the analgesic effect of lidocaine through suppression of microglial activation has been implicated in the development of injury-induced neuropathic pain, its mechanism of action in diabetes-induced tactile allodynia has not yet been completely elucidated. METHODS: To evaluate the effects of lidocaine on microglial response in diabetic neuropathy, streptozotocin (STZ)-injected mice received a continuous infusion of lidocaine (vehicle, 2, or 10%) from day 14 to day 21 after STZ i