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Background Neuropathic pain is relatively common and occurs in approximately 6–8% of the population. It is associated with allodynia and hyperalgesia. Thus, non-pharmacological treatments, such as transcranial direct current stimulation (tDCS) may be useful for relieving pain. Objectives This study aimed to investigate the antiallodynic effect of tDCS in a mice model of neuropathic pain, and the underlying neurotransmission systems that could drive these effects. Methods Male, Swiss mice, weighing 25–35 g, were subjected to partial sciatic nerve ligation (PSNL). Allodynia was assessed using a Von Frey filament (0.6 g). First, the behavioral time-course of these mice was assessed after 5, 10, 15 and 20 min of tDCS (0.5 mA). Second, the mice that underwent PSNL were assigned to either the tDCS (0.5 mA, 15 min) or tDCS sham group, and further assigned to receive either saline or a drug (i.e., naloxone, yohimbine, a-methyl-p-tyrosine, q-chlorophenylalanine methyl ester, caffeine, 1,3-dipropyl-8-cyclopentylxanthine, AM281, AM630, flumazenil, MK-801, or lidocaine). Results The antiallodynic effect of tDCS lasted 2 h and 4 h, after 10 min and 15 or 20 min of treatment, respectively (P < .001, P < .01, and P < .05, respectively). The antiallodynic effect of tDCS was associated with all the systems that were analyzed, i.e., the opioidergic (P < .01), adenosinergic (P < .001), serotonergic (P < .01), noradrenergic (P < .001), cannabinoid (P < .001), GABAergic, and glutamatergic (P < .001) systems. Lidocaine did not reverse the antiallodynic effect of tDCS (P > .05). Conclusion The antiallodynic effect of tDCS was associated with different neurotransmitters systems; the duration of these after-effects depended on the time exposure to tDCS. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a disease caused by a lesion or dysfunction of the nervous system. Antidepressants or anticonvulsants are presently the best available treatments. The mechanism by which antidepressants relieve neuropathic pain remains poorly understood. Using pharmacological and transgenic approaches in mice, we evaluated adrenergic receptor (AR) implication in the action of the tricyclic antidepressant desipramine, the noradrenaline and serotonin reuptake inhibitor venlafaxine, and the noradrenaline reuptake inhibitor reboxetine. Neuropathy was induced by cuff insertion around the sciatic nerve. We showed that chronic antidepressant treatment suppressed cuff-induced allodynia in wild-type mice but not in β2-AR deficient mice, and/or that this antiallodynic action was blocked by intraperitoneal or intrathecal injection of the β2-AR antagonist ICI 118,551 but not by the α2-AR antagonist yohimbine. We also showed that the anticonvulsant gabapentin was still effective in β2-AR deficient mice. Our results demonstrate that β2-ARs are essential for the antiallodynic action of antidepressant drugs.

Although tianeptine, an atypical antidepressant has been reported to have antinociceptive effects, the mode of action is different from that of tricyclic antidepressants despite structural similarities. We examined the antiallodynic effect of intrathecal tianeptine in neuropathic pain rats and determined the involvement of 5-hydroxytryptamine type 7 (5-HT 7 ) receptor of the GABAergic interneurons in the spinal cord. Neuropathic pain was induced by spinal nerve ligation (SNL). After observation of the effect from intrathecal tianeptine, a 5-HT 7 receptor antagonist (SB-269970) was administered intrathecally 10 min before delivery of tianeptine, to determine the contribution of spinal 5-HT 7 receptor on the activity of tianeptine. GAD expression and GABA concentrations were assessed. Intrathecal tianeptine dose-dependently attenuated mechanical allodynia in SNL rats. Pre-treatment with intrathecal SB-269970 reversed the antiallodynic effect of tianeptine. Both GAD65 expression and the GABA concentration in the spinal cord were decreased in neuropathic rats but were increased by tianeptine. Additionally, 5-HT 7 receptor and GAD65 were co-localized in the spinal cord. Intrathecal tianeptine reduces neuropathic pain. 5-HT 7 receptor of the GABAergic interneurons together with GAD65 plays a role in the activity of tianeptine at the spinal cord level. [ABSTRACT FROM AUTHOR]

Highlights: [•] Synthesis of tetrahydropyrido-pyrimidines. [•] Acute nociceptive assays performed. [•] Chronic constriction injury and partial sciatic nerve ligation models in animals were used. [•] Quantification of ED50 for potential analogs determined. [•] Mechanistic studies on inflammatory mediation, oxidative and nitrosative stress performed. [ABSTRACT FROM AUTHOR]

Abstract: We disclose the discovery of a novel series of tetrahydropyrido-pyrazoles that are potent inhibitors of tumour necrosis factor-alpha (TNF-α), nitric oxide and cannabinoid receptor subtype 1 (CB1). We report herein the synthesis and neuropharmacological screening results of the titled compounds in two acute pain and two neuropathic pain models in rodents. Particularly the analogue N-(4-bromophenyl)-3-tert-butyl-5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide (8a) exhibited pronounced acute antinociceptive efficacy, also being effective in chronic constriction injury (ED50 = 23.8 mg/kg) and partial sciatic nerve injury (ED50 = 29.0 mg/kg) models with CB1 receptor activity (IC50 = 49.6 nM) and inhibitory effect on TNF-α (86.4% inhibition at 100 mg/kg). These results suggest the importance of the development of this lead as multi-targeted treatment strategy for neuropathic pain. [Copyright &y& Elsevier]

In this work, synthetic integration of substituted semicarbazides and various aliphatic, aryl and heteroaryl acids into 1,2,4-triazol-5-ones was accomplished. Following the assessment of neurotoxicity and peripheral analgesic activity, the compounds were evaluated in two peripheral models of neuropathic pain, the chronic constriction injury and partial sciatic nerve ligation to assess their antihyperalgesic and antiallodynic potential. ED50 studies undertaken for selected compounds exhibiting promising efficacies ( 1c, 3c and 4a) revealed values ranging from 13.21 to 39.85 mg/kg in four behavioral assays of hyperalgesia and allodynia (spontaneous pain, tactile allodynia, cold allodynia, and mechanical hyperalgesia). Mechanistic studies revealed that the compounds suppressed the inflammatory component of the neuropathic pain inhibiting tumor necrosis factor-alpha and preventing oxidative and nitrosative stress. [ABSTRACT FROM AUTHOR]

Abstract: Neuropathic pain is a chronic pain condition that occurs and persists in a heterogeneous group of etiologically different diseases characterized by a primary lesion or dysfunction of the peripheral or central nervous system. Current treatment options do not provide adequate relief for many patients and a significant number of the agents used have dose limiting side effects. During the course of our work on the synthesis and screening of new drugs for the treatment of neuropathic pain, we have identified 5-(4-nitrophenyl)furoic-2-acid hydrazones which showed significant antiallodynic and antihyperalgesic activities in a chronic constriction injury (CCI) model of neuropathic pain in rat. Synthesized compounds thus represent a promising lead for new drug development for the treatment of neuropathic pain. [Copyright &y& Elsevier]

Abstract: Neuropathic pain is a disease caused by a lesion or dysfunction of the nervous system. Antidepressants or anticonvulsants are presently the best available treatments. The mechanism by which antidepressants relieve neuropathic pain remains poorly understood. Using pharmacological and transgenic approaches in mice, we evaluated adrenergic receptor (AR) implication in the action of the tricyclic antidepressant desipramine, the noradrenaline and serotonin reuptake inhibitor venlafaxine, and the noradrenaline reuptake inhibitor reboxetine. Neuropathy was induced by cuff insertion around the sciatic nerve. We showed that chronic antidepressant treatment suppressed cuff-induced allodynia in wild-type mice but not in β2-AR deficient mice, and/or that this antiallodynic action was blocked by intraperitoneal or intrathecal injection of the β2-AR antagonist ICI 118,551 but not by the α2-AR antagonist yohimbine. We also showed that the anticonvulsant gabapentin was still effective in β2-AR deficient mice. Our results demonstrate that β2-ARs are essential for the antiallodynic action of antidepressant drugs. [Copyright &y& Elsevier]

Abstract: The pituitary adenylate cyclase–activating polypeptide type 1 receptor (PAC1-R) is a member of the 7-transmembrane domain, group 2 G-protein coupled receptor family. PAC1-Rs modulate neurotransmission and neurotrophic actions and have been implicated in both pronociception and antinociception. To better understand the role of PAC1-Rs in pain, PACAP 6-38, a PAC1-R antagonist, was evaluated in several inflammatory and neuropathic pain models after intrathecal (i.t.) administration. PACAP 6-38 potently reduced mechanical allodynia in a neuropathic spinal nerve ligation model (77% ± 15% maximal effect at 12 nmol, P < .01) and was also effective in reducing thermal hyperalgesia in the carrageenan model of inflammatory pain (89% ± 17% maximal effect at 12 nmol, P < .01). Although nociceptive responses were also attenuated with PACAP 6-38 in a dose-dependent manner in models of chronic inflammatory and persistent pain, no effects on motor performance were observed at analgesic doses. Taken together, these data demonstrate that blockade of the PAC1-R/PACAP complex by PACAP 6-38 can effectively attenuate thermal hyperalgesia and mechanical allodynia associated with inflammatory and neuropathic pain states. These results further emphasize that at the level of the spinal cord, PAC1-R activation is pronociceptive. Perspective: This article presents the analgesic profile generated by the blockade, at the spinal cord level, of the PAC-1 receptor by a potent peptide antagonist. This comprehensive data set demonstrates that if small molecule PAC-1 receptor antagonists could be identified, they would potentially produce broad-spectrum analgesia in both inflammatory and neuropathic pain states. [Copyright &y& Elsevier]

Abstract: Neuropathic pain results from injury or dysfunction of the central or peripheral nervous system. The treatment of neuropathic pain is challenging, in part because of its multiple etiologies. The present study explores combinations of the analgesic tramadol and each of four anticonvulsants in the treatment of surgically induced (ligation of the L5 spinal nerve) allodynia in rats. Each of the five drugs studied exhibited a dose-dependent antiallodynic effect. When studied in combination, tramadol and each of two of the anticonvulsants (topiramate and RWJ-333369) interacted synergistically at all three ratios studied, whereas tramadol and each of the other two anticonvulsants (gabapentin and lamotrigine) exhibited a synergistic antiallodynic effect at only one of three ratios investigated. In addition, tramadol and topiramate were found to interact synergistically in a nociceptive pain model, the mouse hot-plate test. These studies suggest the benefit of using combinations of analgesics and anticonvulsants in the relief of neuropathic pain. [Copyright &y& Elsevier]

Background: Natural phenolic compounds in medicinal herbs and dietary plants are antioxidants which play therapeutic or preventive roles in different pathological situations, such as oxidative stress and inflammation. One of the most studied phenolic compounds in the last decade is chlorogenic acid (CGA), which is a potent antioxidant found in certain foods and drinks., Objective: This review focuses on the anti-inflammatory and antinociceptive bioactivities of CGA, and the putative mechanisms of action are described. Ethnopharmacological reports related to these bioactivities are also reviewed., Materials and Methods: An electronic literature search was conducted by authors up to October 2019. Original articles were selected., Results: CGA has been shown to reduce inflammation and modulate inflammatory and neuropathic pain in animal models., Conclusion: The consensus of the literature search was that systemic CGA may facilitate pain management via bolstering antioxidant defenses against inflammatory insults., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)