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The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of methylnaltrexone on remifentanil-induced behavioral hyperalgesia was assessed to distinguish contributions of the peripheral and/or central nervous system to remifentanil-induced hyperalgesia. Phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) in the dorsal root ganglion (DRG) neurons after remifentanil infusion, and the effect of a p38MAPK inhibitor on remifentanil-induced hyperalgesia were analyzed to investigate involvement of p38MAPK in the peripheral mechanisms of remifentanil-induced hyperalgesia. Spinal levels of prodynorphin mRNA after remifentanil infusion, and the effect of the BK2 bradykinin receptor antagonist on remifentanil-induced hyperalgesia were investigated to assess potential spinal mechanisms. The effects of methylnaltrexone and BK2 antagonists on remifentanil-induced exacerbation of post-incisional hyperalgesia were also investigated using behavioral analysis. Remifentanil infusion induced hyperalgesia in the early (4 hours to 2 days) and late (8 to 14 days) post-infusion periods. Methylnaltrexone inhibited hyperalgesia only during the early post-infusion period. p38MAPK phosphorylation was observed in the DRG neuron, and the p38MAPK inhibitor inhibited hyperalgesia during the early post-infusion period. Prodynorphin expression increased in the spinal cord, and a BK2 antagonist inhibited hyperalgesia during the late post-infusion period. Remifentanil-induced exacerbation of incisional hyperalgesia was inhibited by methylnaltrexone and the BK2 antagonist. The present study demonstrated that remifentanil activates peripheral and spinal neurons to promote chronologically distinctive hyperalgesia. p38MAPK phosphorylation in the DRG neuron leads to peripherally-driven hyperalgesia during the early post-infusion period, while spinal dynorphin-bradykinin signaling promotes hyperalgesia during the late post-infusion period.
Learn More >Spinal cord stimulation (SCS) has been shown to provide pain relief for chronic back and leg pain due to failed back surgery syndrome. But many patients with chronic back pain have not had major back surgery or are not good candidates for surgery, and conventional medical management (CMM) provides limited relief. We have termed this condition nonsurgical refractory back pain (NSRBP). Level 1 evidence does not yet exist showing the therapeutic benefit of SCS for NSRBP.
Learn More >The social determinants of health (SDH) are known to differentially impact outcomes from many noncommunicable diseases; however, their potential role in low back pain (LBP) is poorly defined. This review endeavours to comprehensively inform the field of their relevance. Our research question was: "How do the broad range of SDH and chronic LBP (CLBP) relate?" The primary aim of this review was to synthesise evidence of relationships between SDH and the frequency or severity of CLBP. Secondary aims were to identify relationships between SDH and LBP-related disability, work absenteeism, and opioid prescription. We included studies involving adult participants that evaluated relationships between one or more of the SDH and CLBP frequency or LBP outcomes (beyond 3 months). Two reviewers screened studies, extracted data, and assessed risk of bias. We synthesized the results narratively and applied PROGRESS to organise our findings. Database searches identified 7018 records. Forty-one studies were included, containing data from 2,161,617 adults from 17 countries. Twenty-four percent and 19% of the relationships included were classified as having a high risk of bias due to confounding and missing data, respectively. We reported 166 relationships representing the majority of the PROGRESS domains. An array of independent and interdependent relationships between the SDH and CLBP were identified with the strongest evidence for associations related to educational attainment and socioeconomic status. Our findings suggest that greater recognition of the contribution of SDH to disparities in LBP outcomes is warranted and this has the potential to usefully inform strategies to impact burden.
Learn More >Pathological pain is regulated by a balance between pro-algesic and analgesic mechanisms. Interactions between opioid peptide-producing immune cells and peripheral sensory neurons expressing opioid receptors represent a powerful intrinsic pain control in animal models and in humans. Therefore, treatments based on general suppression of immune responses have been mostly unsuccessful. It is highly desirable to develop strategies that specifically promote neuro-immune communication mediated by opioids. Promising examples include vaccination-based recruitment of opioid-containing leukocytes to painful tissue and the local reprogramming of pro-algesic immune cells into analgesic cells producing and secreting high amounts of opioid peptides. Such approaches have the potential to inhibit pain at its origin and be devoid of central and systemic side effects of classical analgesics. In support of these concepts, in this article, we describe the functioning of peripheral opioid receptors, migration of opioid-producing immune cells to inflamed tissue, opioid peptide release, and the consequent pain relief. Conclusively, we provide clinical evidence and discuss therapeutic opportunities and challenges associated with immune cell-mediated peripheral opioid analgesia.
Learn More >Despite the ability of peripheral nerves to regenerate after injury, failure occurs due to an inability of supporting cells to maintain growth, resulting in long-term consequences such as sensorimotor dysfunction and neuropathic pain. Here, we investigate the potential of engaging the cellular adaptive response to hypoxia, via inhibiting its negative regulators, to enhance the regenerative process. Under normoxic conditions, prolyl hydroxylase domain (PHD) proteins 1, 2, and 3 hydroxylate the key metabolic regulator hypoxia inducible factor 1α (HIF1α), marking it for subsequent proteasomal degradation. We inhibited PHD protein function systemically via either individual genetic deletion or pharmacological pan-PHD inhibition using dimethyloxalylglycine (DMOG). We show enhanced axonal regeneration after sciatic nerve crush injury in PHD1 mice, PHD3 mice, and in DMOG-treated mice, and in PHD1 and DMOG-treated mice a reduction in hypersensitivity to cooling after permanent sciatic ligation. Electromyographically, PHD1 and PHD3 mice showed an increased CMAP amplitude one-month post-injury, probably due to protection against denervation induced muscle atrophy, while DMOG-treated and PHD2 mice showed reduced latencies, indicating improved motor axon function. DMOG treatment did not affect the growth of dorsal root ganglion neurites in vitro, suggesting a lack of direct effects of DMOG on axonal regrowth. Enhanced regeneration in vivo was concurrent with an increase in macrophage density, and a shift in macrophage polarization state ratios (from M1-like toward M2-like) in DMOG-treated animals. These results indicate PHD proteins as a novel therapeutic target to improve regenerative and functional outcomes after peripheral nerve injury without manipulating molecular O.
Learn More >Headache diaries and recall questionnaires are frequently used to assess headache frequency and severity in clinical and research settings.
Learn More >Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine.
Learn More >Postoperative pain after total knee arthroplasty (TKA) and total hip arthroplasty (THA) influence patients' rehabilitation and life quality. Although gabapentin has been widely used for analgesia, its efficacy is still controversial in TKA and THA. This meta-analysis was performed to assess the efficacy and safety of gabapentin following TKA and THA.
Learn More >Although migraine is one of the most common primary headaches, its therapy is still limited in many cases. The use of animal models is crucial in the development of novel therapeutic strategies, but unfortunately, none of them show all aspects of the disease, therefore, there is a constant need for further improvement in this field. The application of inflammatory agents on the dura mater is a widely accepted method to mimic neurogenic inflammation in rodents, which plays a key role in the pathomechanism of migraine. Complete Freund's Adjuvant (CFA), and a mixture of inflammatory mediators, called inflammatory soup (IS) are often used for this purpose.
Learn More >Most patients treated with erenumab in clinical practice have chronic migraine (CM). We assessed the rate and possible predictors of conversion from CM to episodic migraine (EM) in a real-life study.
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