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Chronic pain and long-term dementia risk in older adults: Results from a 24-year longitudinal study.
Chronic pain (CP) was associated with cognitive impairment in previous studies. However, the longitudinal association between CP and dementia remains under debate. We aimed to assess the prospective link between CP and long-term dementia risk in a population-based cohort of older participants, considering covariables linked to CP and cognitive functioning.
Learn More >Retraction: "MicroRNA-217 relieved neuropathic pain through targeting toll-like receptor 5 expression", by Wanwei Jiang, Qinghui Wang, Xuemei Yu, Tong Lu, and Pengbo Zhang, J Cell Biochem. 2019; 3009-3017: The above article, published online on 11 December 2018 in Wiley Online Library (doi:10.1002/jcb.27269), has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC. The retraction has been agreed after the authors asked to correct their article. The investigation additionally revealed several flaws and inconsistencies between results presented and experimental methods described. Thus, the editors consider the conclusions of this article to be invalid.
Learn More >Neuropathic pain is a debilitating health concern and there is an urgent need for non-opioid analgesic targets. Our group has identified GPR183 as a novel potential therapeutic target for neuropathic pain. GPR183 is a G-protein coupled receptor that promotes the migration of immune cells in response to its ligand, 7α,25-dihydroxycholesterol (7α,25-OHC). We have shown that GPR183 is upregulated in the dorsal horn spinal cord during neuropathic pain states in rodents and intrathecal injections of 7α,25-OHC is able to induce allodynia in mice in a GPR183-dependent manner. However, the mechanism by which GPR183 activation leads to pain is unknown. These studies aim to elucidate the molecular signaling pathways that contribute to 7α,25-OHC-induced hypersensitivity. Based on previous literature, we hypothesized that GPR183 activation in the spinal cord would activate mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK) and p38, leading to the production of neuroexcitatory cytokines contributing to hypersensitivity.
Learn More >Opioid analgesics are critical for acute and chronic pain management, but important side effects-including tolerance, constipation, respiratory depression, and abuse liability-limit their safety and utility. To provide patients with safer analgesic options, it is critically important to identify of new pharmacotherapeutic strategies to treat pain. Activation of µ-opioid receptors (MORs) in central and peripheral nociceptive pathways mediates opioid analgesia and their critical side effects. Antinociception can also be achieved via selective enhancement of GABAergic signaling at ionotropic GABA receptors. α2 and α3 subunit-containing GABA receptors (α2/α3GABA ), which are co-expressed with MORs in dorsal horn spinal pathways important to nociceptive transmission, can be selectively targeted with novel imidazodiazepine positive allosteric modulators (PAMs), such as MP-III-024, which produces antinociceptive effects with limited behavioral disruption. MP-III-024 co-administered with morphine produces synergistic antinociceptive and anti-hyperalgesic effects. In this study, we evaluated whether MP-III-024/morphine co-administration produces sub-additive or synergistic effects in behavioral tests sensitive to morphine side effects. Herein we report that co-administration of MP-III-024/morphine at a 0.94/1 ratio (synergistic in models of antinociception) produced sub-additive effects in morphine-induced hyperlocomotion and in measures of behavioral disruption in food-maintained operant responding. Ongoing studies are evaluating the effects of MP-III-024/morphine co-administration on tolerance in the hot plate test and in conditioned place preference. These experiments are the first comprehensive preclinical analyses of a dual MOR-α2/α3GABA pharmacotherapy strategy which may increase the therapeutic window between desirable opioid analgesic effects and side effects.
Learn More >The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity or biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein-biased MOR agonists, SR-17018 and SR-14968 stabilize the mu opioid receptor in a wash-resistant, yet antagonist-reversible, G protein signaling state. Furthermore, we demonstrate that these structurally related biased agonists, are noncompetitive for radiolabeled MOR antagonist binding and while they stimulate G protein signaling in mouse brain, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.
Learn More >Chronic pain is a substantial personal and societal burden worldwide. Osteoarthritis (OA) is one of the leading causes of chronic pain and is increasing in prevalence in accordance with a global aging population. In addition to affecting patients' physical lives, chronic pain also adversely affects patients' mental wellbeing. However, there remain no pharmacologic interventions to slow down the progression of OA and pain-alleviating therapies are largely unsuccessful. The presence of low-level inflammation in OA has been recognized for many years as a major pathogenic driver of joint damage. Inflammatory mechanisms can occur locally in joint tissues, such as the synovium, within the sensory nervous system, as well as systemically, caused by modifiable and unmodifiable factors. Understanding how inflammation may contribute to, and modify pain in OA will be instrumental in identifying new druggable targets for analgesic therapies. In this narrative review, we discuss recent insights into inflammatory mechanisms in OA pain. We discuss how local inflammation in the joint can contribute to mechanical sensitization and to the structural neuroplasticity of joint nociceptors, through pro-inflammatory factors such as nerve growth factor, cytokines, and chemokines. We consider the role of synovitis, and the amplifying mechanisms of neuroimmune interactions. We then explore emerging evidence around the role of neuroinflammation in the dorsal root ganglia and dorsal horn. Finally, we discuss how systemic inflammation associated with obesity may modify OA pain and suggest future research directions.
Learn More >To assess the balance sensory organization among patients with migraine, considering the influence of migraine subdiagnosis, otoneurological function, falls, and psychosocial factors.
Learn More >Promising new therapeutic treatments using the fatty acid amide hydrolase (FAAH) inhibitor can be used to relieve symptoms in a patient suffering from a variety of conditions, including but not limited to insomnia, anxiety, fibromyalgia, migraines, arthritis, and other chronic pain conditions. FAAH is responsible for breaking down anandamide, which is an endogenous agonist of the CB1 cannabinoid receptor and analgesic neurotransmitter. The FAAH protein contains a catalytic triad of Ser 241, Ser 217, Lys 142 embedded in its center. The FAAH monomer assumes a twisted 11 strand β-sheet in the middle of the monomer and 24 α-helices surrounding the β-sheets. The Divine Savior Holy Angels MAPS (Modeling A Protein Story) Team modeled the catalytic domain of FAAH using 3D technology. Inhibitors of the FAAH molecules perform better through noncovalent interactions with the triad active site. The inhibitors stop FAAH activity through hydrophobic interactions that result from the active site changing its shape. Noncovalent and reversible inhibitors bring higher selectivity and less unwanted side effects than already studied covalent inhibitors. Non-covalent FAAH inhibitors are currently in development as analgesics lacking the adverse effects of opioid-based analgesics. Further studies are being conducted with selective and potent FAAH inhibitors in order to reduce neurological pain suppression, reduction of cancer cells, and increase feeling of motivation. Currently, the United States is in an opioid crisis that caused 100,000 deaths in the last year, which is why new treatments involving FAAH inhibitors prove promising because they reduce the extreme effects opioid-based drugs present.
Learn More >Substance use disorders (SUDs) and overdose deaths have reached unprecedented levels despite considerable efforts to develop pharmacotherapies for their treatment and prevention. Chemoattractant cytokines ('chemokines') are immune system messengers that can alter the therapeutic and abuse-related effects of opioids and stimulants. Therefore, the aims of this study were to evaluate the effectiveness of Maraviroc, a CCR5 antagonist, and AMD3100, a CXCR4 antagonist, to alter 1) the self-administration of fentanyl, an opioid, and cocaine, a stimulant, using a food versus drug choice procedure and 2) the analgesic effects of fentanyl in a radiant heat assay. Adult male Sprague Dawley rats were trained to respond under a fixed ratio (FR) 5 on one lever to receive an infusion of fentanyl (n=8), and on an alternate lever to receive food (grain-based pellet). The choice procedure consisted of 5 sequential 20-min components, each separated by a 2-min intercomponent interval. Food was available across all five components, with increasing unit doses of fentanyl (0.00032-0.01 mg/kg/infusion) available during components 2-5; no drug was available during component 1. Once responding stabilized, rats underwent a series of drug pretreatment tests, including: naloxone (1, 3.2 mg/kg; IP), haloperidol (0.01-0.1 mg/kg; IP), Maraviroc (1-17.8 mg/kg; IP), and AMD3100 (1-17.8 mg/kg; IP). A separate cohort of 8 adult male Sprague Dawley rats was used to evaluate the effects of Maraviroc (10 mg/kg; IP), and AMD3100 (10 mg/kg; IP), on paw withdrawal latencies in a thermal nociception procedure following cumulative doses of fentanyl (0.01-0.1 mg/kg; IP). In rats responding for food or fentanyl, naloxone reduced fentanyl choice while increasing choice of food, whereas haloperidol had little effect on the choice for fentanyl, but decreased responding on both levers at large doses. Maraviroc and AMD3100 had similar effects all rats tested, effectively reallocating behavior away from the drug and towards the food reinforcer. At the largest dose tested, Maraviroc (17.8 mg/kg; IP) disrupted behavior in the early portions of the session, suggestive of a sedative effect in some animals. Maraviroc and AMD3100 did not significantly modify the analgesic effects of fentanyl during tests of thermal nociception. These data suggest that antagonism of CXCR4 and CCR5 may be of use in the ongoing effort to develop medications for the treatment of SUDs.
Learn More >Small extracellular vesicles (sEVs) are 30-150 nm membranous particles released by a variety of cells and serve as a mediator in intercellular communication between adjacent and distal cells. sEVs carry biomolecular cargo including miRNAs, mRNAs, proteins, and lipids, which are selectively sorted and packaged and mirror the physiological state of the donor cells. Disease states can alter sEV composition affecting the message carried and thereby, its functional impact. Microglia, as the tissue-resident macrophages and primary innate immune cells of the central nervous system, play an important role in neuropathic pain. Here, we investigated alterations in the composition of serum sEVs from a mouse model of neuropathic pain and assessed the functional consequences of sEV uptake by primary cortical microglia.
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