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Bothrops leucurus is the major causative agent of venomous snakebites in Northeastern Brazil. Severe pain is the most frequent symptom in these envenomings, with an important inflammatory component. This work characterized the pronociceptive effects evoked by B. leucurus venom (BLV) in mice and the role of inflammatory mediators in these responses. The nociceptive behaviors were quantified by the modified formalin test. The mechanical hyperalgesia was assessed by the digital von Frey test. Pharmacological assays were performed with different antagonists and synthesis inhibitors to investigate the involvement of inflammatory mediators in both nociceptive events. BLV (1 – 15 µg/paw) injection in mice evoked intense and dose-dependent nociceptive behaviors that lasted for up to 1 h. BLV (10 µg/paw) also caused sustained mechanical hyperalgesia. Histamine and serotonin played a role in the nociception, but not in the BLV-induced mechanical hyperalgesia. Nitric oxide contributed to both responses, but only to the late stages of mechanical hyperalgesia. Eicosanoids were also present in both nociceptive responses. Prostanoid synthesis by COX-1 seemed to be more relevant for the nociception, whereas COX-2 had a more prominent role in the mechanical hyperalgesia. Leukotrienes were the most relevant mediators of BLV-induced mechanical hyperalgesia, hence inhibiting lipoxygenase pathway could be an efficient therapeutic strategy for pain management during envenoming. Our behavioral data demonstrates that BLV promotes nociceptive transmission mediated by biogenic amines, nitric oxide and eicosanoids, and nociceptor sensitization through nitric oxide and eicosanoids. Moreover, phospholipases A (PLA), an important class of toxins present in bothropic venoms, appear to play an important role in the nociceptive and hypernociceptive response induced by BLV.
Learn More >Opioid misuse and overuse has contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids, and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids.
Learn More >Clinician utilization of practice guidelines can reduce inappropriate opioid prescribing and harm in chronic non-cancer pain; yet, implementation of "opioid guidelines" is subpar. We hypothesized that a multi-component quality improvement (QI) augmentation of "routine" system-level implementation efforts would increase clinician adherence to the opioid guideline-driven policy recommendations.
Learn More >Trace amine-associated receptor 1 (TAAR1) plays a critical role in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TAAR1 modulates addiction-like behaviors associated with psychostimulants. However, little is known about whether TAAR1 modulation would regulate the behavioral effects of opioids.
Learn More >Traumatic brain injury (mTBI) is a major public health concern, with mild TBI (mTBI) constituting the vast majority of the injuries. Post-traumatic headache (PTH) is one of the most frequent symptoms that follow a mTBI, occurring in isolation with a tension-type or migraine phenotype, or more often as part of a complex neurobehavioural array of symptoms. The existence of PTH as a separate entity from the primary headaches is still a matter of debate. Classification issues and a lack of methodologically robust epidemiological and clinical studies have made it difficult to elucidate the mechanisms underlying acute and even more persistent PTH (PPTH). Furthermore, psychiatric comorbidities such as post-traumatic stress disorder (PTSD), previous history of migraine, and legal issues often reported by PPTH patients have complicated the understanding of this condition, hence treatment approaches for PTH remain problematic. Recent findings from structural and functional neuroimaging studies have attempted to describe the brain architecture of PPTH, suggesting the involvement of different networks compared to migraine. It also seems that calcitonin gene-related peptide (CGRP) levels are not particularly raised in PPTH, although CGRP monoclonal antibodies have obtained positive initial open-label evidence of efficacy in PPTH, and more trials assessing the efficacy of this class of treatments are underway. The broad overlap between PTH, migraine, and PTSD suggests that research in this field should start with a re-appraisal of the diagnostic criteria, followed by methodologically sound epidemiological and clinical studies. Preclinical research should strive to create more reliable PTH models to support human neuroimaging, neurochemical, and neurogenetic studies, aiming to underpin new pathophysiological hypotheses that may expand treatment targets and improve the management of PTH patients.
Learn More >Intracellular calcium is critical in orchestrating neuronal excitability and analgesia. Carbonic anhydrase-8 (CA8) regulates intracellular calcium signaling through allosteric inhibition of neuronal inositol trisphosphate receptor 1 (ITPR1) to produce profound analgesia. Recently, we reported the "G" allele at rs6471859 represents cis-eQTL regulating alternative splicing of a 1697 bp transcript (CA8-204) with a retained intron, alternative polyadenylation site and a new stop codon producing a functional 26 kDa peptide with an extended exon 3. In this study we show the reversion mutation (G to C) at rs6471859 within the CA8-204 expression vector also produced a stable 1697 bp transcript (CA8-204) coding for a smaller peptide (~ 22 kDa) containing only the first three CA8 exons. Surprisingly, this peptide inhibited ITPR1 (pITPR1) activation, ITPR1-mediated calcium release in vitro; and produced profound analgesia in vivo. This is the first report showing CA8-204 codes for a functional peptide sufficient to regulate calcium signaling and produce profound analgesia.
Learn More >Spinal cord stimulation (SCS) is a neuromodulation technology widely used in the treatment of intractable chronic pain syndromes. SCS is now being applied more broadly as a possible therapy for a range of indications, including neurological, cardiac, and gastrointestinal disorders. Ongoing research in this field is critical in order to gain further insights into the mechanisms of SCS, determine its role in new indications, and refine programming techniques for the optimization of therapeutic outcomes.
Learn More >Sensory information is transmitted from peripheral nerves, through the spinal cord, and up to the brain ("bottom up" pathway). Some of this information may be modulated by "top-down" projections from the brain to the spinal cord. Discovering endogenous mechanisms for reducing pain and itch holds enormous potential for developing new treatments. However, neurons mediating the top-down inhibition of pain are not well understood, nor has any such pathway been identified for itch sensation. Here we identify a novel population of GABAergic neurons in the ventral brainstem, distinguished by prodynorphin expression, which we named LJA5. LJA5 neurons provide the only known inhibitory projection specifically to lamina I of the spinal cord, which contains sensory neurons that transmit pain and itch information up to the brain. Chemogenetically activating LJA5 neurons in male mice reduces capsaicin-induced pain and histamine-induced itch. Identifying this new pathway opens new treatment opportunities for chronic, refractory pain and pruritis. This article is protected by copyright. All rights reserved.
Learn More >Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gα and Gα activity and their downstream effectors, while having no effect on G signaling and βarrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor.
Learn More >The purpose of this study was to enhance the understanding of the process that physical therapists undertake when creating and disseminating exercise programs for older adults with chronic back pain.
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