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Intrathecal opioid pumps have been used in the management of severe chronic pain for more than 40 years. Numerous studies have shown significant therapeutic effects alongside tolerable side effects. In the last decades, life expectancy has increased in many countries in the world. With an aging population, the question arises whether effects equal to those in younger patients can also be achieved in elderly patients.
Learn More >Migraine pain is thought to result from activation of meningeal nociceptors that might involve dural mast cell degranulation and release of proteases and pronociceptive mediators. Tryptase, the most abundant dural mast cell protease, has been demonstrated to stimulate dural mast cells, as well as trigeminal nociceptors by activating the protease activated receptor 2. Mast cell or neuronal protease activated receptors 2 may therefore represent a novel target for migraine treatment. In this study, we characterized and evaluated a novel protease activated receptor 2 monoclonal antibody as a preventive anti-migraine pain therapy in preclinical models.
Learn More >OnabotulinumtoxinA (BTX) has become a mainstream treatment for chronic migraine (CM). Patients often have varied expectations for treatment success but little is known about how these initial impressions influence continuation of therapy.
Learn More >Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/β-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of β-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated β-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1β in DRG. PAC also upregulated rAxin2 in mice. Furthermore, β-catenin was expressed in neurons, including calcitonin gene-related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and β-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP.
Learn More >Identifying the optimal fremanezumab treatment strategy is crucial in treating patients with migraines. The optimal strategy was investigated by assessing the cumulative 50% reduction rate (50%CRR), cumulative 75% reduction rate (75%CRR), reduction in the number of migraine days, treatment-related adverse events, and serious adverse events in patients treated with fremanezumab 225 mg monthly (225 mg), 675 mg monthly (675 mg), 900 mg monthly (900 mg), a single high dose of 675 mg (S675mg), 675 mg at baseline with 225 mg monthly (675/225 mg), and placebo. Biomedical databases were searched for randomized controlled trials on this topic, and data were individually extracted. Risk ratios and mean differences were used to present the pooled results. The surface under the cumulative ranking curve (SUCRA) was used to determine the effects of the medication strategies of fremanezumab. Five trials (n = 3404) were used to form a six-node network meta-analysis. All fremanezumab medication strategies displayed significantly higher cumulative 50% reduction rates than the placebo. The SUCRA revealed that treatment with 675 mg yielded the highest 50%CRR value (mean rank = 2.5). S675 mg was the only treatment with significantly higher 75%CRR reduction rate than placebo, whereas the SUCRA for 225 mg displayed the highest mean rank (2.2). Moreover, 225 mg (mean rank = 2.2) and S675 mg (mean rank = 2.2) presented lower probabilities of serious adverse events. Collectively, S675mg and 225 mg exhibited the optimal balance between efficacy and safety within three months. Long-term efficacy and safety remain unclear, and future studies should further evaluate the long-term outcomes.
Learn More >The newly designed fentanyl derivative [( ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide] (NFEPP) was recently shown to produce analgesia selectively via peripheral mu-opioid receptors (MOR) at acidic pH in rat inflamed tissues. Here, we examined the pH-dependency of NFEPP binding to brain MOR and its effects on bone cancer-induced pain in mice. The IC of NFEPP to displace bound [H]-DAMGO was significantly higher compared to fentanyl at pH 7.4, but no differences were observed at pH 5.5 or 6.5. Intravenous NFEPP (30-100 nmol/kg) or fentanyl (17-30 nmol/kg) inhibited heat hyperalgesia in mice inoculated with B16-F10 melanoma cells. The peripherally-restricted opioid receptor antagonist naloxone-methiodide reversed the effect of NFEPP (100 nmol/kg), but not of fentanyl (30 nmol/kg). The antihyperalgesic effect of NFEPP was abolished by a selective MOR- (cyprodime), but not delta- (naltrindole) or kappa- (nor-binaltorphimine) receptor antagonists. Ten-fold higher doses of NFEPP than fentanyl induced maximal antinociception in mice without tumors, which was reversed by the non-restricted antagonist naloxone, but not by naloxone-methiodide. NFEPP also reduced heat hyperalgesia produced by fibrosarcoma- (NCTC 2472) or prostate cancer-derived (RM1) cells. These data demonstrate the increased affinity of NFEPP for murine MOR at low pH, and its ability to inhibit bone cancer-induced hyperalgesia through peripheral MOR. In mice, central opioid receptors may be activated by ten-fold higher doses of NFEPP.
Learn More >TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by µ-opioid receptors through the signaling of Gβγ proteins, thereby reducing TRPM3-mediated pain. We show here that Gβγ directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with Gβγ. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in Gβ that are individually necessary for TRPM3 inhibition by Gβγ. The 10-amino-acid Gβγ-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that Gβγ proteins exert on TRPM3 channels.
Learn More >To investigate the effect of intranasal oxytocin on chronic pelvic pain in a randomized, double-blind, within-subject crossover trial. Aims included: (1) determine intranasal oxytocin's effect on pain intensity and pain interference relative to placebo; (2) assess feasibility and acceptability.
Learn More >Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia – an animal model of migraine – and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription. The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways.
Learn More >A recent study found that merely possessing a placebo analgesic reduces pain. The current study tested for a possible moderator of this effect. Specifically, does the mere possession of a placebo analgesic affect pain for individuals with and without immediate prior experience with the pain task? Healthy participants (N=127) were randomized to prior pain (PP) condition or without prior pain (No-PP) condition. In the PP condition, participants first did a preliminary trial of a cold pressor test (CPT) to induce direct experience with this pain stimulus. Then they were randomized to possess an inert cream described as either an analgesic cream or an anti-itch cream (pain-irrelevant control object). Participants then completed the main CPT. In the No-PP condition, participants underwent identical procedures and randomization except that they did not do a preliminary CPT, thus having no immediate prior CPT pain experience. We found a significant prior pain experience and possession status interaction effect on placebo analgesia. Participants in the No-PP condition showed evidence of lower pain when they merely possessed an analgesic cream than an anti-itch cream. Such mere possession effect was not found in the PP condition. The impact of expectancy and emotion on the underlying process are discussed. PERSPECTIVE: This article presents a novel finding that prior pain exposure and mere possession of a placebo analgesic predicted placebo analgesia. It offers a novel perspective on the time course of placebo effect. It provides practical implications on potential pain intervention for clinicians and paradigm design for researchers of placebo study.
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