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Tolerance to cannabinoid agonists can develop through desensitization of the cannabinoid receptor 1 (CB) following prolonged administration. Desensitization results from phosphorylation of CB by a G protein-coupled receptor kinase (GRK), and subsequent association of the receptor with arrestin. Mice expressing a mutant form of CB, in which the serine residues at two putative phosphorylation sites necessary for desensitization have been replaced by non-phosphorylatable alanines (S426A/S430A), display reduced tolerance to Δ-tetrahydrocannabinol (Δ-THC). Tolerance to the antinociceptive effects of WIN55,212-2 was delayed in S426A/S430A mutants using the tail-flick and formalin tests. However, tolerance to the antinociceptive effects of once daily CP55,940 injections was not significantly delayed in S426A/S430A mutant mice using either of these tests. Interestingly, the dose response curve shifts for the hypothermic and antinociceptive effects of CP55,940 that were induced by chronic treatment with this agonist in wild-type mice were blocked in S426A/S430A mutant mice. Assessment of mechanical allodynia in mice exhibiting chronic cisplatin-evoked neuropathic pain found that tolerance to the anti-allodynic effects WIN55,212-2 but not CP55,940 was delayed in S426A/S430A mice compared to wild-type littermates. Despite these deficits in tolerance, S426A/S430A mutant mice eventually developed tolerance to both WIN55,212-2 and CP55,940 for all pain assays that were examined, suggesting that other mechanisms likely contribute to tolerance for these cannabinoid agonists. These findings suggest that GRK- and βarrestin2-mediated desensitization of CB may strongly contribute to the rate of tolerance to the antinociceptive effects of WIN55,212-2, and raises the possibility of agonist-specific mechanisms of cannabinoid tolerance.
Learn More >Chemotherapy-induced oral thermal hyperalgesia (OTH) is a common and debilitating side effect of platinum-based anticancer agents. This study evaluated the efficacy of oral cryotherapy in preventing OTH during oxaliplatin chemotherapy infusion.
Learn More >Pain management is complex regardless of whether the pain is acute or chronic in nature or non-cancer or cancer related. In addition, relatively few pain pharmacotherapy options with adequate efficacy and safety data currently exist. Consequently, interest in the role of NMDA receptor antagonists as a pharmacological pain management strategy has surfaced. This narrative review provides an overview of the NMDA receptor and elaborates on the pharmacotherapeutic profile and pain management literature findings for the following NMDA receptor antagonists: ketamine, memantine, dextromethorphan, and magnesium. The literature on this topic is characterized by small studies, many of which exhibit methodological flaws. To date, ketamine is the most studied NMDA receptor antagonist for both acute and chronic pain management. Although further research about NMDA receptor antagonists for analgesia is needed and the optimal dosage/administration regimens for these drugs have yet to be determined, ketamine appears to hold the most promise and may be of particular value in the perioperative pain management realm.
Learn More >Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) that exerts analgesic and anti-inflammatory actions. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed primarily in nociceptors, mediates the action of proalgesic and inflammatory agents. Ibuprofen metabolism yields the reactive compound, ibuprofen-acyl glucuronide, which, like other TRPA1 ligands, covalently interacts with macromolecules. To explore whether ibuprofen-acyl glucuronide contributes to the ibuprofen analgesic and anti-inflammatory actions by targeting TRPA1, we used in vitro tools (TRPA1-expressing human and rodent cells) and in vivo mouse models of inflammatory pain. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited calcium responses evoked by reactive TRPA1 agonists, including allyl isothiocyanate (AITC), in cells expressing the recombinant and native human channel and in cultured rat primary sensory neurons. Responses by the non-reactive agonist, menthol, in a mutant human TRPA1 lacking key cysteine-lysine residues, were not affected. In addition, molecular modeling studies evaluating the covalent interaction of ibuprofen-acyl glucuronide with TRPA1 suggested the key cysteine residue C621 as a probable alkylation site for the ligand. Local administration of ibuprofen-acyl glucuronide, but not ibuprofen, in the mouse hind paw attenuated nociception by AITC and other TRPA1 agonists and the early nociceptive response (phase I) to formalin. Systemic ibuprofen-acyl glucuronide and ibuprofen, but not indomethacin, reduced phase I of the formalin response. Carrageenan-evoked allodynia in mice was reduced by local ibuprofen-acyl glucuronide, but not by ibuprofen, whereas both drugs attenuated PGE levels. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited the release of IL-8 evoked by AITC from cultured bronchial epithelial cells. The reactive ibuprofen metabolite selectively antagonizes TRPA1, suggesting that this novel action of ibuprofen-acyl glucuronide might contribute to the analgesic and anti-inflammatory activities of the parent drug.
Learn More >Activation of cannabinoid CB receptors suppresses pathological pain but also produces unwanted side effects, including tolerance and physical dependence. Inhibition of fatty-acid amide hydrolase (FAAH), the major enzyme catalyzing the degradation of anandamide (AEA), an endocannabinoid, and other fatty-acid amides, suppresses pain without unwanted side effects typical of direct CB agonists. However, FAAH inhibitors have failed to show efficacy in several clinical trials suggesting that the right partnership of FAAH inhibition and pathology has yet to be identified. We compared efficacy of chronic treatments with a centrally penetrant FAAH inhibitor (URB597), a peripherally-restricted FAAH inhibitor (URB937) and an orthosteric pan-cannabinoid agonist (WIN55,212-2) in suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel. Each FAAH inhibitor suppressed the development of paclitaxel-induced neuropathic pain and reduced the maintenance of already established allodynia with sustained efficacy. Tolerance developed to the anti-allodynic efficacy of WIN55,212-2, but not to that of URB597 or URB937, in each dosing paradigm. Challenge with the CB antagonist rimonabant precipitated CB-dependent withdrawal in paclitaxel-treated mice receiving WIN55,212-2 but not URB597 or URB937. When dosing with either URB597 or URB937 was restricted to the development of neuropathy, paclitaxel-induced allodynia emerged following termination of drug delivery. These observations suggest that both FAAH inhibitors were anti-allodynic rather than curative. Moreover, neither URB597 nor URB937 impeded the ability of paclitaxel to reduce breast (4T1) or ovarian (HeyA8) tumor cell line cytotoxicity. In fact, URB597 and URB937 alone reduced 4T1 tumor cell line cytotoxicity, albeit with low potency, and the dose matrix of each combination with paclitaxel was synergistic in reducing 4T1 and HeyA8 tumor cell line viability according to Bliss, Highest Single Agent (HSA) and Loewe additivity models. Both FAAH inhibitors synergized with paclitaxel to reduce 4T1 and HeyA8 tumor cell line viability without reducing viability of non-tumor HEK293 cells. Neither FAAH inhibitor reduced viability of non-tumor HEK293 cells in either the presence or absence of paclitaxel, suggesting that nonspecific cytotoxic effects were not produced by the same treatments. Our results suggest that FAAH inhibitors reduce paclitaxel-induced allodynia without the occurrence of CB-dependence in vivo and may, in fact, enhance the anti-tumor actions of paclitaxel in vitro.
Learn More >Abdominal pain associated with low-grade inflammation is frequently encountered in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) during the remission phase. Current treatments are generally weakly effective. Therefore, new therapeutic approaches are needed. The role of Cav3.2 voltage-dependent calcium channels, which have been shown to be important in other chronic pain contexts, was investigated in a murine model of colonic hypersensitivity (CHS) associated with low-grade inflammation.
Learn More >Based on few clinical trials, flunarizine is considered a first-line prophylactic treatment for migraine in several guidelines. In this meta-analysis, we examined the pooled evidence for its effectiveness, tolerability, and safety. Prospective randomized controlled trials of flunarizine as a prophylaxis against migraine were identified from a systematic literature search, and risk of bias was assessed for all included studies. Reduction in mean attack frequency was estimated by calculating the mean difference (MD), and a series of secondary outcomes-including adverse events (AEs)-were also analyzed. The database search yielded 879 unique records. Twenty-five studies were included in data synthesis. We scored 31/175 risk of bias items as "high," with attrition as the most frequent bias. A pooled analysis estimated that flunarizine reduces the headache frequency by 0.4 attacks per 4 weeks compared with placebo (5 trials, 249 participants: MD -0.44; 95% confidence interval -0.61 to -0.26). Analysis also revealed that the effectiveness of flunarizine prophylaxis is comparable with that of propranolol (7 trials, 1151 participants, MD -0.08; 95% confidence interval -0.34 to 0.18). Flunarizine also seems to be effective in children. The most frequent AEs were sedation and weight increase. Meta-analyses were robust and homogenous, although several of the included trials potentially suffered from high risk of bias. Unfortunately, reporting of AEs was inconsistent and limited. In conclusion, pooled analysis of data from partially outdated trials shows that 10-mg flunarizine per day is effective and well tolerated in treating episodic migraine-supporting current guideline recommendations.
Learn More >The commercial formulation of sumatriptan nasal spray is an effective option for migraine patients requiring or preferring a non-oral route of drug administration, but its utility is limited by poor absorption and tolerability issues. DFN-02, a new formulation of sumatriptan 10 mg nasal spray, is co-formulated with a permeation enhancer that gives it pharmacokinetics comparable to subcutaneous sumatriptan. As reported previously, DFN-02 was significantly better than placebo on multiple efficacy endpoints at 2 h postdose, including pain freedom, absence of the most bothersome symptom, and pain relief, and its safety and tolerability profiles were excellent.
Learn More >To understand the efficacy of zolmitriptan applied with Adhesive Dermally Applied Microarray (ADAM) in treating types of migraine (those with severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or migraine present upon awakening) that are historically considered to be less responsive to oral medications.
Learn More >Migraine is a debilitating disease that affects almost 15% of the population worldwide and is the first cause of disability in people under 50 years of age, yet its etiology and pathophysiology remain incompletely understood. Recently, small molecules and therapeutic antibodies that block the calcitonin gene-related peptide (CGRP) signaling pathway have reduced migraine occurrence and aborted acute attacks of migraine in clinical trials and provide prevention in patiens with episodic and chronic migraine. Heterogeneity is present within each diagnosis and a patient's response to treatment, suggesting migraine as a final common pathway potentially activated by multiple mechanisms, e.g. not all migraine attacks respond or are prevented by anti-CGRP pharmacological interventions. Consequently, other unique mechanisms central to migraine pathogenesis may present new targets for drug development. Pituitary adenylate cyclase-activating peptide (PACAP) is an attractive novel target for treatment of migraines. We generated a specific, high affinity, neutralizing monoclonal antibody (ALD1910) with reactivity to both PACAP38 and PACAP27. In vitro, ALD1910 effectively antagonizes PACAP38 signaling through the PAC1-R, VPAC1-R, and VPAC2-R. ALD1910 recognizes a non-linear epitope within PACAP and blocks its binding to the cell surface. To test ALD1910 antagonistic properties directed against endogenous PACAP, we developed an umbellulone-induced rat model of neurogenic vasodilation and parasympathetic lacrimation. In vivo, this model demonstrates that the antagonistic activity of ALD1910 is dose-dependent, retaining efficacy at doses as low as 0.3 mg/kg. These results indicate that ALD1910 represents a potential therapeutic antibody to address PACAP-mediated migraine.
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