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It is often assumed that there are two types of pain patients: those who respond well to efficacious pain therapies and those who do not respond at all, with few people in the middle. This assumption is based on research that claims that changes in pain intensity have a bimodal distribution. The claim of bimodality has led to calls for a change in how pain clinical trials are designed and analyzed, for example, performing "responder" analyses instead of comparing group means to evaluate the treatment effect. We analyzed data from four clinical trials, two each of duloxetine and pregabalin, for chronic musculoskeletal and neuropathic pain conditions to critically examine the claim of bimodality of the distribution of change in pain intensity. We found that the improper construction of histograms, using unequal bin widths, was the principal flaw leading to the bimodality claim, along with the use of the oft-criticized baseline observation carried forward (BOCF) method for imputing missing data also serving as a contributing factor. Properly constructed histograms of absolute change in pain intensity using equal bin widths, combined with more principled methods for handling missing data, resulted in distributions that had a more unimodal appearance. While our findings neither support nor refute the hypothesis that distinct populations of "responders" and "non-responders" to pain interventions exist, the analyses presented in earlier work do not provide support for this hypothesis, nor for the recommendation that pain clinical trials prioritize "responder" analyses, a less efficient analysis strategy.
Learn More >To provide a narrative review of clinical development programs for non-oral, non-injectable formulations of dihydroergotamine (DHE) for the treatment of migraine.
Learn More >Opioids are commonly used to provide analgesia for cancer pain, and functional opioid receptors have been identified on natural killer (NK) cells, the lymphocytes responsible for surveillance and elimination of cancer cells. Opioids also bind to other lymphocyte receptors, such as Toll-like receptor (TLR)-4. Here, we characterized the effects of morphine on primary human NK cell cytotoxicity and mediator release, which occur through classical opioid receptor or TLR4 signaling.
Learn More >Opioid drugs are the gold standard for the management of pain, but their use is severely limited by dangerous and unpleasant side effects. All clinically available opioid analgesics bind to and activate the mu-opioid receptor (MOR), a heterotrimeric G-protein-coupled receptor, to produce analgesia. The activity of these receptors is modulated by a family of intracellular RGS proteins or regulators of G-protein signaling proteins, characterized by the presence of a conserved RGS Homology (RH) domain. These proteins act as negative regulators of G-protein signaling by serving as GTPase accelerating proteins or GAPS to switch off signaling by both the Gα and βγ subunits of heterotrimeric G-proteins. Consequently, knockdown or knockout of RGS protein activity enhances signaling downstream of MOR. In this review we discuss current knowledge of how this activity, across the different families of RGS proteins, modulates MOR activity, as well as activity of other members of the opioid receptor family, and so pain and analgesia in animal models, with particular emphasis on RGS4 and RGS9 families. We discuss inhibition of RGS proteins with small molecule inhibitors that bind to sensitive cysteine moieties in the RH domain and the potential for targeting this family of intracellular proteins as adjuncts to provide an opioid sparing effect or as standalone analgesics by promoting the activity of endogenous opioid peptides. Overall, we conclude that RGS proteins may be a novel drug target to provide analgesia with reduced opioid-like side effects, but that much basic work is needed to define the roles for specific RGS proteins, particularly in chronic pain, as well as a need to develop newer inhibitors.
Learn More >Painful distal symmetrical polyneuropathy (DPN) is a frequent complication of type-2 diabetes mellitus (T2DM) that commonly presents as neuropathic pain and loss of skin nerve fibers. However, there are limited therapies to effectively treat DPN and many of the current animal models of T2DM-induced DPN do not appear to mirror the human disease. Thus, we validated a DPN mouse model induced by a cafeteria-style diet plus low-doses of streptozotocin (STZ). Female C57BL/6J mice were fed either standard (STD) diet or obesogenic cafeteria (CAF) diet for 32 weeks, starting at 8 weeks old. Eight weeks after starting diets, CAF or STD mice received either four low-doses of STZ or vehicle. Changes in body weight, blood glucose and insulin levels, as well as oral glucose- and insulin-tolerance tests (OGTT and ITT) were determined. The development of mechanical hypersensitivity of the hindpaws was determined using von Frey filaments. Moreover, the effect of the most common neuropathic pain drugs was evaluated on T2DM-induced mechanical allodynia. Finally, the density of PGP -9.5 (a pan-neuronal marker) axons in the from the hindpaw glabrous skin was quantified. At 22-24 weeks after STZ injections, CAF + STZ mice had significantly higher glucose and insulin levels compared to CAF + VEH, STD + STZ, and STD + VEH mice, and developed glucose tolerance and insulin resistance. Skin mechanical sensitivity was detected as early as 12 weeks post-STZ injections and it was significantly attenuated by intraperitoneal acute treatment with amitriptyline, gabapentin, tramadol, duloxetine, or carbamazepine but not by diclofenac. The density of PGP-9.5 nerve fibers was reduced in CAF + STZ mice compared to other groups. This reverse translational study provides a painful DPN mouse model which may help in developing a better understanding of the factors that generate and maintain neuropathic pain and denervation of skin under T2DM and to identify mechanism-based new treatments.
Learn More >Apelin is the endogenous ligand for APJ, a G-protein-coupled receptor. Apelin gene and protein are widely distributed in the central nervous system and peripheral tissues. The role of apelin in chronic inflammatory pain is still unclear. In the present study, a mouse model of complete Freund's adjuvant (CFA)-induced inflammatory pain was utilized, and the paw withdrawal latency/threshold in response to thermal stimulation and Von Frey filament stimulation were recorded after intrathecal (i.t.) injection of apelin-13 (0.1, 1, and 10 nmol/mouse). The mRNA and protein expression, concentration of glutamic acid (Glu), and number of c-Fos immunol staining in lumbar spinal cord (L4/5) were determined. The results demonstrated that gene expression in the lumbar spinal cord was down-regulated in the CFA pain model. Apelin-13 (10 nmol/mouse, i.t.) alleviated CFA-induced inflammatory pain, and it exhibited a more potent antinociceptive effect than apelin-36 and (pyr)apelin-13. The antinociception of apelin-13 could be blocked by APJ antagonist apelin-13(F13A). I.T. apelin-13 attenuated the increased levels of , , and genes expression, Glu concentration, and NMDA receptor 2B (GluN2B) protein expression caused by CFA. Apelin-13 significantly reduced the number of Fos-positive cells in laminae III and IV/V of the dorsal horn. This study indicated that i.t. apelin-13 exerted an analgesic effect against inflammatory pain, which was mediated by activation of APJ, and inhibition of Glu/GluN2B function and neural activity of the spinal dorsal horn.
Learn More >Clinical and preclinical studies have revealed that local administration of opioid agonists into peripheral tissue attenuates inflammatory pain. However, few studies have examined whether peripherally restricted opioids are effective in reducing mechanical allodynia and hyperalgesia that usually follows nerve injury. The aim of the present study was to determine whether the mechanical responsiveness of C-fiber mechanical nociceptors innervating skin under neuropathic pain conditions is depressed by direct activation of delta opioid receptors (DORs) on their peripheral terminals. A murine model of peripheral neuropathic pain was induced with a spared nerve (tibial) injury, in which mice survived 7 or 28 days after surgery before electrophysiological testing began. Control groups comprised naïve and sham-operated animals. An ex vivo preparation of mouse plantar skin with attached tibial nerve was used to examine electrophysiologically the effects of the selective DOR agonist, deltorphin II, on the response properties of individual cutaneous C-fiber nociceptors. In contrast to naïve and sham-operated animals, deltorphin II induced an inhibition of the mechanical responsiveness of C-fiber mechanical nociceptors innervating skin under neuropathic conditions. The effects of deltorphin II were concentration-dependent and prevented by pretreatment with naltrindole indicating DOR-mediated inhibitory effects of deltorphin II. Our results provide the first direct evidence for expression of functional DORs on mechanical nociceptors innervating skin in an animal model of neuropathic pain.
Learn More >Opioids are the most effective analgesics used in the clinical management of cancer pain or non-cancer pain. However, chronic opioids therapy can cause many side effects including respiratory depression, nausea, sedation, itch, constipation, analgesic tolerance, hyperalgesia, high addictive potential, and abuse liability. Opioids exert their effects through binding to the opioid receptors belonging to the G-protein coupled receptors (GPCRs) family, including mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR). Among them, MOR is essential for opioid-induced analgesia and also responsible for adverse effects of opioids. Importantly, MOR can form heterodimers with other opioid receptors and non-opioid receptors and , and has distinct pharmacological properties, different binding affinities for ligands, downstream signaling, and receptor trafficking. This mini review summarized recent progress on the function of Mu opioid receptor heterodimers, and we proposed that targeting mu opioid receptor heterodimers may represent an opportunity to develop new therapeutics, especially for chronic pain treatment.
Learn More >Toll-like receptor 4 (TLR4) recognizes exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) and initiates the innate immune response. Opioid receptors (μ, δ, and κ) activate inhibitory G-proteins and relieve pain. This review summarizes the following types of TLR4/opioid receptor pathway crosstalk: (a) Opioid receptor agonists non-stereoselectively activate the TLR4 signaling pathway in the central nervous system (CNS), in the absence of lipopolysaccharide (LPS). Opioids bind to TLR4, in a manner parallel to LPS, activating TLR4 signaling, which leads to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression and the production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. (b) Opioid receptor agonists inhibit the LPS-induced TLR4 signaling pathway in peripheral immune cells. Opioids operate as pro-inflammatory cytokines, resulting in neuroinflammation in the CNS, but they mediate immunosuppressive effects in the peripheral immune system. It is apparent that TLR4/opioid receptor pathway crosstalk varies dependent on the cell type and activating stimulus. (c) Both the TLR4 and opioid receptor pathways activate the mitogen-activated protein kinase (MAPK) pathway. This crosstalk is located downstream of the TLR4 and opioid receptor signaling pathways. Furthermore, the classic opioid receptor can also produce pro-inflammatory effects in the CNS via MAPK signaling and induce neuroinflammation. (d) Opioid receptor agonists induce the production of high mobility group box 1 (HMGB1), an endogenous TLR4 agonist, supporting intercellular (neuron-to-glia or glia-to-neuron) interactions. This review also summarizes the potential effects of TLR4/opioid receptor pathway crosstalk on opioid analgesia, immune function, and gastrointestinal motility. Opioids non-stereoselectively activate the TLR4 pathway, and together with the subsequent release of pro-inflammatory cytokines such as IL-1 by glia, this TLR4 signaling initiates the central immune signaling response and modifies opioid pharmacodynamics. The DAMP HMGB1 is associated with the development of neuropathic pain. To explain morphine-induced persistent sensitization, a positive feedback loop has been proposed; this involves an initial morphine-induced amplified release of IL-1β and a subsequent exacerbated release of DAMPs, which increases the activation of TLR4 and the purinergic receptor P2X7R. Opioid receptor (μ, δ, and κ) agonists are involved in many aspects of immunosuppression. The intracellular TLR4/opioid receptor signaling pathway crosstalk induces the formation of the β-arrestin-2/TNF receptor-associated factor 6 (TRAF6) complex, which contributes to morphine-induced inhibition of LPS-induced TNF-α secretion in mast cells. A possible molecular mechanism is that the TLR4 pathway initially triggers the formation of the β-arrestin-2/TRAF6 complex, which is amplified by opioid receptor signaling, suggesting that β-arrestin-2 acts as a functional component of the TLR4 pathway.
Learn More >Migraine is a common neurological disorder characterized by recurrent headache episodes that accompany sensory-motor disturbances, such as higher sensitivity to touch and light, extremity heaviness or weakness, and speech or language disabilities. Worldwide, migraine is one of the top 10 causes of disability and hence poses a huge economic burden to society. On average, migraine occurs in 12% of population but its occurrence is sexually dimorphic, as it is two to three times more prevalent in women than in men. This female to male ratio of migraine prevalence is age- and sex hormone-dependent. Advancements in understanding migraine pathogenesis have also revealed an association with both genetics and epigenetics. The severity of migraine, in terms of its attack duration, headache intensity, frequency, and occurrence of migraine-associated symptoms, has generally been reported to be greater in women. Sex differences in migraine disability and comorbidities, such as psychiatric disorders, have also been noted in some population-based studies. However, research on sex-related differences in response to migraine treatments is relatively scarce. Although a general observation is that women consume more medication than men for migraine treatment, strategies for the use of abortive and preventive medications for migraine are generally similar in both sexes. This narrative review summarizes available findings on sexually distinct responses to abortive and prophylactic pharmacotherapy of migraine. Basic experimental data and clinical findings will be presented, and potential mechanisms underlying sex-based responses will be discussed to highlight the importance and value of sex-based treatment in migraine research and practice.
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