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Noxious pain signals are transduced in the peripheral nervous system as action potentials, which rely on the activities of voltage-gated sodium channels (NaVs). Blocking NaVs is thus a valuable strategy for pain treatment. Here, we report the characterization of a novel NaVs antagonist, 2-(2-(diethylamino)ethyl)indeno[1,2,3-de]phthalazin-3(2H)-one (C65780), and investigation of its action mechanisms. C65780 inhibited the resting NaV1.7, NaV1.8, and NaV1.9 channels with IC50s of 11.3 ± 0.4 μM, 2.7 ± 0.3 μM and 19.2 ± 2.3 μM, respectively. Mechanistic analysis revealed that C65780 quickly bound to its high-affinity receptor site in NaV1.7 as formed by the fast inactivation process and stabilized the channels in a slowly recovering state, for which it facilitated NaV1.7 channels' inactivation by shifting their inactivation-voltage relationship in the hyperpolarizing direction, increasing the plateau proportion of inactivated channels, and blunting their time-dependent recovery. The slow inactivation of NaV1.7, however, is not involved in the action of C65780. In DRG neurons, C65780 also inhibited activity of NaVs, thus dampening neuronal excitability. These effects parlayed into a broad efficacy of orally administrated C65780 in various models of pain, with an efficacy comparable to the antidepressant/neuropathic pain drug Amitriptyline. Excitingly, C65780 demonstrated weaker inactivated state inhibition of related NaV1.4 and NaV1.5 channels compared to amitriptyline, and no toxicity or inhibition of locomotion in a forced-swimming test was observed in mice at pain-relieving doses. These results demonstrate that C65780 acts by trapping NaVs in the inactivated and slowly-recovering state to produce pain relief and may represent an excellent starting compound for developing analgesics.
Learn More >In 2019, senior leaders within the US Department of Veterans Affairs and the US Department of Defense commissioned the update of a clinical practice guideline for managing chronic multisymptom illness. Clinical experts were assembled across both agencies to systematically review evidence and to develop treatment recommendations based on that evidence. This effort resulted in the development of 29 evidence-based recommendations for providing care for individuals with chronic multisymptom illness.
Learn More >Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM.
Learn More >Spinal cord stimulation (SCS)-induced analgesia was characterized, and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats. The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20% and 80% motor thresholds. Various frequencies (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) of SCS were similarly effective. SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation. SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid. The analgesic effect of 2 Hz was abolished by μ or κ opioid receptor antagonist. The effect of 100 Hz was prevented by a κ antagonist, and that of 10 kHz was blocked by any of the μ, δ, or κ receptor antagonists, suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors.
Learn More >Chronic pain remains an unresolved problem. Current treatments have limited efficacy. Thus, novel therapeutic targets are urgently required for the development of more effective analgesics. An increasing number of studies have proved that sirtuin 1 (SIRT1) agonists can relieve chronic pain. In this review, we summarize recent progress in understanding the roles and mechanisms of SIRT1 in mediating chronic pain associated with peripheral nerve injury, chemotherapy-induced peripheral neuropathy, spinal cord injury, bone cancer, and complete Freund's adjuvant injection. Emerging studies have indicated that SIRT1 activation may exert positive effects on chronic pain relief by regulating inflammation, oxidative stress, and mitochondrial dysfunction. Therefore, SIRT1 agonists may serve as potential therapeutic drugs for chronic pain.
Learn More >Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in the management of the disease, we still lack curative treatments for it. Thus, there is an unmet societal demand to identify further details of its pathogenesis to thereby pave the way for novel therapeutic approaches with favorable side effect profiles. It is commonly accepted that dysfunction of the complex cutaneous barrier plays a central role in the development of AD; therefore, the signaling pathways involved in the regulation of this quite complex process are likely to be involved in the pathogenesis of the disease and can provide novel, promising, yet unexplored therapeutic targets. Thus, in the current review, we aim to summarize the available potentially AD-relevant data regarding one such signaling pathway, namely cutaneous opioidergic signaling.
Learn More >The bidirectional relationship between anxiety and chronic pain in youth is well-known, but how anxiety contributes to the maintenance of pediatric chronic pain needs to be elucidated. Sensitivity to pain traumatization (SPT), an individual's propensity to develop responses to pain that resemble a traumatic stress response, may contribute to the mutual maintenance of anxiety and pediatric chronic pain. A clinical sample of youth (aged 10-18 years) with chronic pain completed a measure of SPT at baseline and rated their anxiety and pain characteristics for seven consecutive days at baseline and at three-month follow-up. Multiple linear regression analyses were conducted to model whether SPT moderated the relationship between baseline anxiety and pain intensity, unpleasantness, and interference three months later. SPT significantly moderated the relationship between anxiety and pain intensity. High anxiety youth with high SPT reported increased pain intensity three months later, while high anxiety youth with low SPT did not. High anxiety youth who experience pain as potentially traumatizing are more likely to report higher pain intensity three months later than high-anxiety youth who do not. Future research should examine whether children's propensity to become traumatized by their pain predicts the development of chronic pain and response to intervention.
Learn More >Chronic pain remains a major health problem and is currently facing slow drug innovation. New drug treatments should address not only the sensory-discriminative but also functional and motivational-affective components of chronic pain. In a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSNL), we analyzed sensory and functional-like outcomes by hindpaw mechanical stimulation and automated gait analysis (CatWalk). We characterized over time a reward-seeking task based on diminished motivation for natural reinforcers (anhedonic-like behavior). To differentiate the appetitive ("wanting") and consummatory ("liking") aspects of motivational behavior, we quantified the latency and number of approaches to eat white chocolate, as well as the eating duration and amount consumed. We explored a putative chronic pain-induced dysregulation of monoamine function by measuring monoamine levels in the nucleus accumbens (NAc), a well-known brain reward area. Finally, we investigated the role of sigma-1 receptor (σR) modulation, a nonopioid target, in these multiple dimensions by genetic deletion and pharmacological dose-response studies. After 6 weeks, PSNL increased the approach latency and reduced the consumption of white chocolate in 20-25% of the mice, while around 50-60% had one or the other parameter affected independently. After 10 weeks, sham-operated mice also displayed anhedonic-like behavior. PSNL was associated with reduced extracellular baseline dopamine and increased norepinephrine in the NAc and with a suppression of increased dopamine and serotonin efflux in response to the rewarding stimulus. Genetic and pharmacological blockade of σR relieved these multiple alterations in nerve-injured mice. We comprehensively describe sensory, functional, and depression-like impairment of key components of motivated behavior associated with nerve injury. We provide a neurochemical substrate for the depressed mesocorticolimbic reward processing in chronic pain, with a potentially increased translational value. Our results also highlight σR for the therapeutic intervention of neuropathic pain.
Learn More >Chronic pain represents a global health problem with a considerable economic burden. The relation of alcohol intake and chronic pain conditions was assessed in several studies with conflicting results. We used dose-response meta-analysis techniques to answer the question of whether alcohol intake is related to chronic pain occurrence.
Learn More >Spinal cord stimulation (SCS) involves electrical stimulation of the dorsal spinal cord to disrupt the transmission of ascending pain signals. SCS has been used successfully to manage a variety of chronic pain conditions, but its efficacy in the treatment of pain syndromes in patients with cancer has not been established because most studies have involved a limited number of patients. The purpose of this study was to assess the efficacy of SCS in a large group of patients with cancer.
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