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All children experience pain, and although many recover quickly, some go on to develop chronic pain. Adolescent chronic pain is a growing epidemic. It is unknown why some adolescents recover without incident and others experience persistent pain. Although unexplored, early life adversity may contribute to the development and maintenance of chronic pain. This study investigated the effects and underlying neurobiological mechanisms of an early life stressor on nociceptive (pain) sensitivity and emotional function in male and female Sprague-Dawley rats. Using maternal separation (MS) as an established model of early life stress, we addressed two aims: investigation of the effects of MS on behavior (anxiety and pain sensitivity), and investigation of the effects of MS on mRNA and pathophysiological changes associated with an acutely painful stimulus. Our results indicate that MS increased anxiety-like behavior and altered nociceptive responsivity in adolescent rats, with decreased mechanical withdrawal thresholds indicative of heightened and prolonged pain-related behavior. The MS groups also demonstrated increased expression of genes involved in regulating the stress and fight-or-flight response, mood, and neuroplasticity; as well as increased levels of inflammatory markers. We conclude that nociception, both at the behavioral and molecular level, is altered in response to the MS stressor.
Learn More >Several reports support the idea that µ- and δ-opioid receptors (ORs) may exist as heterodimers in brain regions involved in pain signaling. The unique pharmacology of these heteromers may present a novel analgesic target. However, the role of µ-δ heteromers in sensory neurons involved in pain and opioid analgesia remains unclear, particularly during neuropathic pain. We examined the effects of spinal nerve injury on µ-δ heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a µ-δ heteromer-targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased µ-δ heteromer expression in L5 DRG, but increased heteromer levels in uninjured L4 DRG. Importantly, in SNL rats, subcutaneous (s.c.) injection of CYM51010 inhibited mechanical hypersensitivity in a dose-related manner (EC50: 1.09 mg/kg) and also reversed heat hyperalgesia and attenuated ongoing pain (2 mg/kg, s.c.). HEK-293T cells surface-labeled with µ- and δ-ORs internalized both receptors after exposure to CYM51010. In contrast, in cells transfected with µ-OR alone, CYM51010 was significantly less effective at inducing receptor internalization. Electrophysiologic studies showed that CYM51010 inhibited the C-component and windup phenomenon in spinal wide-dynamic range neurons of SNL rats. The pain inhibitory effects of CYM51010 persisted in morphine-tolerant rats, but was markedly attenuated in µ-OR knockout mice. Our studies show that spinal nerve injury may increase µ-δ heterodimerization in uninjured DRG neurons and that µ-δ heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance.
Learn More >The proper identification of chronic migraine is one of the mainstays for general practitioners. This study therefore aims to assess the epidemiology and determinants of chronic migraine in primary care in Italy by testing five operational case definition algorithms.
Learn More >Prospective cohort study OBJECTIVE.: The aims of this study were to evaluate the outcome of surgical as well as non-surgical treatment for patients with lumbar herniated disc (LHD) or lumbar spinal stenosis (LSS) after two years and to identify predictors for non-success.
Learn More >The present study characterized the behavioral pharmacology of a novel, mixed-action delta-selective (78:1) opioid receptor agonist, BBI-11008. This glycopeptide drug candidate was tested in assays assessing antinociception (acute, inflammatory, and neuropathic pain-like conditions) and side-effect endpoints (respiratory depression and drug self-administration).
Learn More >Herpetic neuralgia is a painful condition following herpes zoster disease, which results from Varicella-zoster virus reactivation in the dorsal or trigeminal sensory ganglia. Nevertheless, the pathophysiological mechanisms involved in herpetic neuralgia are not well understood. Recently, we identified, that neuroimmune-glia interactions in the sensory ganglion is a critical mechanism for the development of herpetic neuralgia. Here, we investigate the contribution of S100A9, a well-known pro-inflammatory molecule produced by myeloid cells, for the development of herpetic neuralgia using a murine model of HSV-1 infection. We found that cutaneous HSV-1 infection results in an increase of S100A9 expression in the Dorsal Root Ganglia (DRGs). Infiltrating neutrophils into the DRGs were the main source of S100A9 post HSV-1 infection. Functionally, genetic or pharmacological inhibition of S100A9 impairs the development of HSV-1 infection-induced mechanical pain hypersensitivity. Finally, we found that the pronociceptive role of S100A9 in herpetic neuralgia depends on the TLR4/TNF pathway. These results unraveled previously unknown mechanisms involved in the pathophysiology of herpetic neuralgia and indicate that S100A9 might be an important target for novel therapies aiming acute herpetic neuralgia.
Learn More >While persistent opioid use after surgery has been the subject of a large number of studies, it is unknown how much variability in the definition of persistent use impacts the reported incidence across studies. The objective was to evaluate the incidence of persistent use estimated with different definitions using a single cohort of postoperative patients, as well as the ability of each definition to identify patients with opioid-related adverse events.
Learn More >The ATP1A2 coding α2 subunit of Na,K-ATPase, which is predominantly located in astrocytes, is a causative gene of familial hemiplegic migraine type 2 (FHM2). FHM2 model mice (Atp1a2 ) are susceptible to cortical spreading depression (CSD), which is profoundly related to migraine aura and headache. However, astrocytic properties during CSD have not been examined in FHM2 model mice. Using Atp1a2 crossed with transgenic mice expressing G-CaMP7 in cortical neurons and astrocytes (Atp1a2 ), we analyzed the changes in Ca concentrations during CSD. The propagation speed of Ca waves and the percentages of astrocytes with elevated Ca concentrations in Atp1a2 were higher than those in wild-type mice. Increased percentages of astrocytes with elevated Ca concentrations in Atp1a2 may contribute to FHM2 pathophysiology.
Learn More >The objective of this study is to investigate the association of clinical markers of obesity and weight trajectories with chronic musculoskeletal pain (CMP). This is a cross-sectional study using baseline data from ELSA-Brasil MSK cohort. CMP was evaluated at nine body sites (neck, shoulders, upper back, elbows, lower back, wrists/hands, hips/thighs, knees, ankles/feet), and defined as pain lasting > 6 months in the past year. General and abdominal obesity levels were classified according to accepted cut-offs for body mass index (BMI), waist circumference (WC) and waist-height ratio (WHtR). Binomial and multinomial logistic regressions tested for associations with CMP at any site, at ≥ 3 sites (multisite) and in upper + lower limbs + axial skeleton (generalized). A total of 2899 participants (mean age 56.0 ± 8.93) were included, 55.0% reported CMP, 19.1% had multisite, and 10.3% had generalized CMP. After adjustments for sex, age, education, physical activity and depressive symptoms, nearly all the investigated markers of obesity were associated with any CMP, multisite and generalized CMP, with strongest associations being observed for general obesity level II/III: OR 2.08 (95% CI 1.45-2.99), OR 3.19 (95% CI 2.06-4.94) and OR 3.65 (2.18-6.11), respectively. Having excess weight currently or both at age 20 and currently was also associated with all CMP presentations. Associations of greater magnitude were consistently observed at higher obesity levels and longer exposures to excess weight (dose-response). These results may support the contribution of obesity-derived mechanical and inflammatory mechanisms of CMP, and indicate a role for the accumulation of exposure to excess weight across the adult life course.
Learn More >TRPM8 is the main ion channel responsible for cold transduction in the somatosensory system. Nerve terminal availability of TRPM8 determines cold sensitivity, but how axonal secretory organelles control channel delivery remains poorly understood. Here we examine the distribution of TRPM8 and trafficking organelles in cold-sensitive peripheral axons and disrupt trafficking by targeting the ARF-GEF GBF1 pharmacologically or the small GTPase RAB6 by optogenetics. In axons of the sciatic nerve, inhibition of GBF1 interrupts TRPM8 trafficking and increases association with the trans-Golgi network, LAMP1, and Golgi satellites, which distribute profusely along the axonal shaft. Accordingly, both TRPM8-dependent ongoing activity and cold-evoked responses reversibly decline upon GBF1 inhibition in nerve endings of corneal cold thermoreceptors. Inhibition of RAB6, which also associates to Golgi satellites, decreases cold-induced responses in vivo. Our results support a non-conventional axonal trafficking mechanism controlling the availability of TRPM8 in axons and cold sensitivity in the peripheral nervous system.
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