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The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in ∼0.4% of present-day Britons, where they are associated with heightened pain sensitivity.
Learn More >Peripheral neuropathies (PN) and primary headaches (PH) are common comorbidities in inflammatory bowel disease (IBD) patients. We aimed to evaluate whether PN and PH affect the same subgroups of IBD patients.
Learn More >The purpose of this review is to summarize the up-to-date pain management options and recommendations for the challenging disease, endometriosis.
Learn More >Primary care providers, general pediatric neurologists, and other related subspecialty providers require a clear understanding of pediatric migraine with typical aura and its variants.
Learn More >Muscle pain is the most prevalent type of pain in the world, but treatment remains ineffective. Thus, it is relevant to develop trustable animal models to understand the involved pain mechanisms. Therefore, this study characterised the nociception and inflammation in a traumatic muscle injury model in rats. A single blunt trauma impact on the right gastrocnemius muscle of male Wistar rats (250-350 g) was used as model for muscle pain. Animals were divided into four groups (sham/no treatment; sham/diclofenac 1%; injury/no treatment; injury/diclofenac 1%) and the topical treatment with a cream containing 1% monosodium diclofenac (applied at 2, 6, 12, 24, and 46 h after muscle injury; 200 mg/muscle) was used as an anti-inflammatory control. Nociception (mechanical and cold allodynia, or nociceptive score) and locomotor activity were evaluated at 26 and 48 h after injury. Also, inflammatory and oxidative parameters were evaluated in gastrocnemius muscle and the creatine kinase (CK) activity and lactate/glicose levels in rat's serum and plasma, respectively. Muscle injury caused mechanical and cold allodynia, and increased nociceptive scores, without inducing locomotor impairment. This model also increased the inflammatory cells infiltration (seen by myeloperoxidase and N-acetyl-β-D-glucosaminidase activities and histological procedure), nitric oxide, interleukin (IL)-1β, IL-6, and dichlorofluorescein fluorescence in muscle samples; and CK activity and lactate/glicose ratio. The treatment with 1% monosodium diclofenac reduced inflammatory cells infiltration, dichlorofluorescein fluorescence and lactate/glicose levels. Thus, we characterised the traumatic muscle injury as a reproducible model of muscle pain, which makes it possible to evaluate promising antinociceptive and anti-inflammatory therapies.
Learn More >Osteoarthritis (OA) is the most common cause of joint pain. Animal models and relevant assays for measurement of pain-related behaviours are important tools for studies of mechanisms inducing and sustaining pain in OA. The aim of this study was to evaluate two different assessments of weight bearing; stationary and during locomotion, and to explore their feasibility to detect analgesic effects in vivo. Two fundamentally different mouse models of joint arthritis were investigated; surgical transection of the anterior cruciate ligament (ACLT) resulting in destabilization of the joint with subsequent structural deterioration resembling OA, and monoarthritis induced by injection of Complete Freund´s Adjuvant (CFA) into the ankle joint capsule.
Learn More >We tested the hypothesis that high molecular weight hyaluronan (HMWH) binds to and signals via cluster of differentiation 44 receptor (CD44), to attenuate nociceptor function, in the setting of inflammation. We found that HMWH attenuates prostaglandin E (PGE)-induced mechanical hyperalgesia, in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense to CD44 mRNA and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuate anti-hyperalgesia induced by HMWH. HMWH signaling is dependent on CD44 clustering in lipid rafts, leading to activation of downstream second messenger signaling pathways. Methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts, attenuates HMWH-induced anti-hyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K), also attenuates HMWH-induced anti-hyperalgesia. Our results demonstrate the central role of CD44 in HMWH-induced anti-hyperalgesia and establish its second messengers as novel therapeutic targets for the treatment of pain.We have previously demonstrated that high molecular weight hyaluronan (HMWH) attenuates inflammatory and neuropathic hyperalgesia. In this study we demonstrate that HMWH attenuates PGE-hyperalgesia is mediated by its action at CD44, and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1) and phospholipases (phospholipases Cε and Cγ1), in nociceptors of male and female rats. These findings contribute to our understanding of the anti-hyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.
Learn More >Treatment for fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain, but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine (Mir), which is presumed to disinhibit 5-HT release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2, postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4-5 days after the cessation of treatments. The repeated Mir-treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of siRNA adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia, but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that Mir could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions. SIGNIFICANCE STATEMENT: This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)-induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the anti-hyperalgesia, while other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS-model.
Learn More >Evidence from several novel opioid agonists and knockout animals suggest that improved opioid therapeutic window, notably for analgesia versus respiratory depression, can be caused by ligand bias downstream of activation of the mu-opioid receptor (MOR) towards G-protein signaling and away from other pathways such as arrestin recruitment. Here, we argue that published claims of opioid bias based on application of the operational model of agonism are frequently confounded by failure to consider the assumptions of the model. These include failure to account for intrinsic efficacy and ceiling effects in different pathways, distortions introduced by analysis of amplified (G-protein) versus linear (arrestin) signaling mechanisms, and non-equilibrium effects in a dynamic signaling cascade. We show on both theoretical and experimental grounds that reduced intrinsic efficacy that is unbiased across different downstream pathways does produce apparent but erroneous MOR ligand bias towards G-protein signaling, and the weaker the G-protein partial agonism the greater is the apparent bias. Experimentally, such apparently G-protein biased opioids have been shown to exhibit low intrinsic efficacy for G-protein signaling when ceiling effects are properly accounted for. Nevertheless, such agonists do display an improved therapeutic window for analgesia versus respiratory depression. Reduced intrinsic efficacy for G-proteins rather than any supposed G-protein bias provides a more plausible, sufficient explanation for the improved safety. Moreover, genetic models of G-protein biased opioid receptors and replication of previous knockout experiments suggest that reduced or abolished arrestin recruitment does not improve therapeutic window for analgesia versus respiratory depression. SIGNIFICANCE STATEMENT: Efforts to improve safety of mu-opioid analgesics has focused on agonists that show signaling bias for the G-protein pathway versus other signaling pathways. This review provides theoretical and experimental evidence showing that failure to properly consider the assumptions of the operational model of bias commonly leads to large distortions and overestimation of actual bias. We show that low intrinsic efficacy is a major determinant of these distortions and pursuit of appropriately reduced intrinsic efficacy should lead development of safer opioids.
Learn More >Activated astrocytes play important roles in chronic post-surgical pain (CPSP). Recent studies have shown reactive astrocytes are classified into A1 and A2 phenotypes, but their precise roles in CPSP remain unknown. In this study, we investigated the roles of spinal cord A1 and A2 astrocytes and related mechanisms in CPSP.
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