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Pharmacological tools for chronic visceral pain management are still limited and inadequate. A3 adenosine receptor (A3AR) agonists are effective in different models of persistent pain. Recently their activity has been related to the block of N-type voltage-gated Ca channels (Cav2.2) in dorsal root ganglia (DRG) neurons. The present work aimed to evaluate the efficacy of A3AR agonists in reducing post-inflammatory visceral hypersensitivity in both male and female rats. Colitis was induced by the intra-colonic instillation of 2,4-dinitrobenzenesulfonic acid (DNBS; 30 mg in 0.25 ml 50% EtOH). Visceral hypersensitivity was assessed by measuring the viscero-motor response and the abdominal withdrawal reflex to colorectal distension. The effects of A3AR agonists (MRS5980 and Cl-IB-MECA) were evaluated over time after DNBS injection and compared to that of the selective Cav2.2 blocker PD173212, and the clinically used drug linaclotide. A3AR agonists significantly reduced DNBS-evoked visceral pain both in the post-inflammatory (14 and 21 days after DNBS injection) and persistence (28 and 35 days after DNBS) phases. Efficacy was comparable to effects induced by linaclotide. PD173212 fully reduced abdominal hypersensitivity to control values, highlighting the role of Cav2.2. The effects of MRS5980 and Cl-IB-MECA were completely abolished by the selective A3AR antagonist MRS1523. Furthermore, patch-clamp recordings showed that A3AR agonists inhibited Cav2.2 in DRG neurons isolated from either control or DNBS-treated rats. The effect on Ca current was PD173212-sensitive and prevented by MRS1523. A3AR agonists are effective in relieving visceral hypersensitivity induced by DNBS, suggesting a potential therapeutic role against abdominal pain.
Learn More >The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT) receptor agonism, to 'reset' areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.
Learn More >ALD403 is a genetically engineered, humanized immunoglobulin G1 monoclonal antibody that inhibits the action of human calcitonin gene-related peptide (CGRP). Clinical trial data indicate that ALD403 is effective as a preventive therapy for migraine and has an acceptable safety profile. For preclinical characterization of ALD403, rabbit antibodies targeting α-CGRP were humanized and modified to eliminate Fcγ-receptor (FcγR) and complement interactions. The ability of ALD403 to inhibit CGRP-induced cyclic adenosine monophosphate (cAMP) production was assessed using a cAMP bioassay (Meso Scale Discovery). The IC50 for inhibition of cAMP release was 434 and 288 pM with the rabbit-human chimera antibody and the humanized ALD403, respectively. ALD403 inhibited α-CGRP binding with an IC50 of 4.7 x 10-11 and 1.2 x 10-10 for the α-CGRP and AMY1 receptors, respectively. ALD403 did not induce antibody-dependent cellular cytotoxicity nor complement-dependent cytotoxicity and did not stably interact with any of the FcγR mediating these functions, exhibiting only weak binding to FcγRI. ALD403 significantly lowered capsaicin-induced blood flow responses in rodents at all time points starting at 5 minutes post-application in a dose-dependent manner. In conclusion, ALD403 is a potent functional ligand inhibitor of α-CGRP‒driven pharmacology. SIGNIFICANCE STATEMENT: α-CGRP blockade by ALD403 was assessed via radiolabeled ligand displacement, in vitro inhibition of cell signaling, and in vivo inhibition of capsaicin-induced vasodilation. Lack of engagement of Fc-mediated immune-effector functions by ALD403 was shown.
Learn More >Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here a drug-design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II-VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CA II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.
Learn More >We estimated the use of prescribed analgesics and adjuvants among nursing home residents without cancer who reported pain at their admission assessment, in relation to resident-reported pain severity.
Learn More >Opioid analgesics remain the mainstay for managing intractable chronic pain, but their use is limited by detrimental side effects such as analgesic tolerance and hyperalgesia. Calcium-dependent synaptic plasticity is a key determinant in opiates tolerance and hyperalgesia. However, the exact substrates for this calcium-dependent synaptic plasticity in mediating these maladaptive processes are largely unknown. Canonical transient receptor potential 1, 4, and 5 (TRPC1, 4, 5) proteins assemble into heteromultimeric nonselective cation channels with high Ca permeability and influence various neuronal functions. However, whether and how TRPC1/4/5 channels contribute to the development of opiates tolerance and hyperalgesia remains elusive. Here, we show that TRPC1/4/5 channels contribute to the generation of morphine tolerance and hyperalgesia. Chronic morphine exposure leads to upregulation of TRPC1/4/5 channels in the spinal cord. Spinally expressed TRPC1, TPRC4, and TRPC5 are required for chronic morphine-induced synaptic long-term potentiation (LTP) as well as remodeling of synaptic spines in the dorsal horn, thereby orchestrating functional and structural plasticity during the course of morphine-induced hyperalgesia and tolerance. These effects are attributed to TRPC1/4/5-mediated Ca elevation in the spinal dorsal horn induced by chronic morphine treatment. This study identifies TRPC1/4/5 channels as a promising novel target to prevent the unwanted morphine tolerance and hyperalgesia.
Learn More >Monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) or its receptor have emerged as effective and well-tolerated preventive medications for migraine. The key role played by CGRP has been recently demonstrated also in the pathophysiology of cluster headache (CH), paving the way for studies aimed to investigate the effectiveness of mABs targeting CGRP also in CH. However, no trials have been conducted so far to test the efficacy and tolerability of erenumab as CH preventive treatment.
Learn More >Many parallel-group studies of migraine prophylaxis using valproate medications were reported in recent decades. This meta-analysis assessed the efficacy and safety of valproate medications for migraine prophylaxis in adults.
Learn More >Understanding nonsteroidal antiinflammatory drug (NSAID) use and impact on common rheumatic and arthritic conditions is critical to reconciling their appropriate use with their potentially serious adverse effects. NSAIDs have a profound impact on the treatment of connective tissue disorders because of their ability to address the underlying cause with specific benefits of decreasing stiffness and inflammation, and improving mobility. NSAID use is twice as common as opioid use, and inappropriate use of NSAIDs is widespread. NSAID use should be monitored and the impact understood to mitigate the risks. NSAID discontinuation should be evidence based and individualized to specific requirements.
Learn More >The Chronic pain epidemic is a pressing public health crises facing the United States. Currently, more than 100 million Americans suffer from chronic pain, with chronic pain being among the most prevalent conditions and the leading cause of disability. Chronic pain disproportionately affects certain populations including women, low-income individuals, and older adults. This article focuses primarily on new molecular entities in development targeting various chronic pain receptors and new delivery technologies.
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