Neuropharmacology最新文献

{"title":"Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in inadequately/poorly responding patients with chronic schizophrenia: Results from a randomized, double-blind, placebo-controlled, phase 3, international clinical trial.","authors":"Ravi Anand, Alessio Turolla, Giovanni Chinellato, Francesca Sansi, Arjun Roy, Richard Hartman","doi":"10.1016/j.neuropharm.2024.110275","DOIUrl":"10.1016/j.neuropharm.2024.110275","url":null,"abstract":"<p><strong>Background: </strong>Evenamide, a glutamate modulator, is currently in phase 3 of development as add-on treatment to antipsychotics in patients with inadequate response or treatment-resistant schizophrenia. This study was designed to determine if patients with chronic schizophrenia inadequately responding to a second-generation antipsychotic would benefit from add-on treatment with evenamide at a dose of 30 mg bid.</p><p><strong>Methods: </strong>Study 008A was a prospective, 4-week, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of oral doses of evenamide of 30 mg bid in patients with chronic schizophrenia treated at stable therapeutic doses of a second-generation antipsychotic. Outpatients aged ≥18 years, both males and females, with a diagnosis of schizophrenia (DSM-V), who had been receiving antipsychotics for at least 2 years at stable doses, but still symptomatic (PANSS 70-85, CGI-S 4-6, predominant positive symptoms), were eligible for the study. Patients were randomised equally to evenamide 30 mg or placebo, given bid, after completing a 21-day screening period. The primary outcome (change from baseline in PANSS total score) was assessed weekly, with the primary endpoint at 4 weeks.</p><p><strong>Results: </strong>A total of 291 patients were enrolled, of which 11 (3·8%) discontinued prematurely, overall. Add-on treatment with evenamide was associated to a statistically significant (the absolute difference of the two treatment groups for the PANSS Total at Day 29, primary efficacy endpoint, was = 2·5 [p-value<0.05] that is associated with a Cohen's d effect size = 0·33) and clinically meaningful benefit compared to placebo across all efficacy measures, and was well tolerated.</p><p><strong>Conclusion: </strong>The demonstration of statistically significant and clinically meaningful benefit of evenamide, a glutamate modulator, as add-on treatment in patients with chronic schizophrenia inadequately responding to their second-generation antipsychotic may represent a new treatment paradigm for this population.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110275"},"PeriodicalIF":4.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toluene is a cerebral artery constrictor acting via BK channels.","authors":"Andrew A Shaw, Jeffery D Steketee, Anna N Bukiya, Alex M Dopico","doi":"10.1016/j.neuropharm.2024.110272","DOIUrl":"10.1016/j.neuropharm.2024.110272","url":null,"abstract":"<p><p>Acute intoxication by toluene usually follows intentional inhalation to achieve a \"high\", which may lead to repeated use due to toluene's reinforcing properties. In both acute and chronic intoxication brain function is primarily affected. Neuronal and glial elements participate in toluene's reinforcing properties and chronic toxicity, yet the targets underlying acute toxicity remain unknown. Many signs of toluene's acute toxicity overlap with those of brain ischemia. Moreover, two studies in humans who abused toluene reveal brain hypoperfusion in middle cerebral artery (MCA) territories. Hypoperfusion, however, may result from either excessive vasoconstriction/increased vasodilation. Using rat and mouse models, we demonstrate that toluene at concentrations reached during recreational inhalation (8000 ppm) significantly decreases (-8%) MCA diameter in vivo in male and female animals. Using GC-MS, we determined toluene blood levels from inhalation (0.09-127 mM) and then show that <1 mM toluene constricts ex vivo-pressurized MCA independently of endothelium. Toluene action is blunted by deletion of KCNMA1, which codes for BK channels, key regulators of MCA diameter, and upon selective channel blockade by 1 μM paxilline. Lastly, when applied onto an isolated membrane patch several minutes after patch-excision from the SM cell, submM toluene reduces mildly yet statistically significantly (P < 0.05) both steady-state activity (-15%) and unitary current amplitude (-20%) of MCA myocyte BK channels. Thus, BK channels themselves and their immediate proteolipid microenvironment suffice for these drug actions. Collectively, data unveil a direct inhibition of MCA myocyte BK currents by intoxicating levels of toluene, which determines, or at least contributes to, MCA constriction by toluene levels reached during inhalation by humans who suffer acute brain intoxication.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110272"},"PeriodicalIF":4.6,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute kappa opioid receptor blocking disrupts the pro-cognitive effect of cannabidiol in neuropathic rats.","authors":"Serena Boccella, Antimo Fusco, Federica Ricciardi, Andrea Maria Morace, Roozbe Bonsale, Michela Perrone, Ida Marabese, Danilo De Gregorio, Carmela Belardo, Luca Posa, Laura Rullo, Fabiana Piscitelli, Vincenzo di Marzo, Alessandro Nicois, Brenda Marfella, Luigia Cristino, Livio Luongo, Francesca Guida, Sanzio Candeletti, Gabriella Gobbi, Patrizia Romualdi, Sabatino Maione","doi":"10.1016/j.neuropharm.2024.110265","DOIUrl":"10.1016/j.neuropharm.2024.110265","url":null,"abstract":"<p><p>Cannabidiol has been shown to ameliorate neuropathic pain and its affective components. Previous studies highlighted the pharmacological interaction between the CBD and opioid system, particularly the MOR, but the understanding of the interaction between CBD and kappa opioid receptor (KOR), physiologically stimulated by the endogenous opioid dynorphin, remains elusive. We assessed the pharmacological interactions between CBD and nor-BNI, a selective KOR antagonist in a rat neuropathic pain model. We show an increase in dynorphin peptide and its KOR receptors in the hippocampus' dentate gyrus (DG) of neuropathic rats showing allodynia, and memory deficits. Consistent with these findings, neuropathic pain was associated with long-term potentiation (LTP) impairment in the entorhinal cortex-DG, also referred to as the lateral perforant pathway (LPP). Moreover, a downregulation of the endocannabinoid 2-AG and an upregulation of the cannabinoid CB1 receptors in the DG were detected in neuropathic pain animals. Either an acute KOR antagonist administration or one-week CBD treatment normalized dynorphin levels and improved affective symptoms, LTP and receptor expression, whereas only CBD showed an anti-allodynic effect. In addition, CBD normalized the SNI-induced changes in neuroplasticity as well as endocannabinoid and GABA levels in the DG. Noteworthy, the acute blockade of the KOR carried out after CBD repeated administration causes the re-installment of some neuropathic condition symptoms. As a whole, these original results indicate a critical relationship between the adaptive changes in the hippocampus produced by CBD and the need to maintain the recovered physiological dynorphin tone to preserve the therapeutic effect of CBD in neuropathic rats.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110265"},"PeriodicalIF":4.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heat shock proteins in chronic pain: From molecular chaperones to pain modulators.","authors":"Nivedita Verma, Deepak Chouhan, Allani Meghana, Vinod Tiwari","doi":"10.1016/j.neuropharm.2024.110263","DOIUrl":"10.1016/j.neuropharm.2024.110263","url":null,"abstract":"<p><p>Chronic pain is the most prevalent and complex clinical disorder,affecting approximately 30% of people globally. Various intricate alterations in nociceptive pathways responsible for chronic pain are linked to long-term tissue damage or injury to the peripheral or central nervous systems. These include remolding in the phenotype of cells and fluctuations in the expression of proteins such as ion channels, neurotransmitters, and receptors. Heat shock proteins are important molecular chaperone proteins in cell responses to stress, including inflammation, neurodegeneration, and pain signaling. They play a key role in activating glial and endothelial cells and in the production of inflammatory mediators and excitatory amino acids in both peripheral and central nervous systems. In particular, they contribute to central sensitization and hyperactivation within the dorsal horn of the spinal cord. The expression of some HSPs plays a remarkable role in upregulating pain response by acting as scavengers of ROS, controlling inflammatory cytokines. Different HSPs act by different mechanisms and several important pathways have been implicated in targeting HSPs for the treatment of neuropathic pain including p38-mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), brain-derived neurotrophic factors (BDNF). We summarize the role of HSPs in various preclinical and clinical studies and the crosstalk of HSPs with various nociceptors and other pain models. We also highlighted some artificial intelligence tools and machine learning-assisted drug discovery methods for rapid screening of HSPs in various diseases. Focusing on HSPs could lead to the development of new therapeutics that modulate pain responses and enhance our understanding of pain in various pathological conditions and neurological disorders.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110263"},"PeriodicalIF":4.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR1 antagonist as a potential modulator of inflammatory, autophagic, and apoptotic markers in spinal cord injury","authors":"Ahmed Hasan ,&nbsp;Alberto Repici ,&nbsp;Anna Paola Capra ,&nbsp;Deborah Mannino ,&nbsp;Valentina Bova ,&nbsp;Antonio Catalfamo ,&nbsp;Michela Campolo ,&nbsp;Irene Paterniti ,&nbsp;Emanuela Esposito ,&nbsp;Alessio Ardizzone","doi":"10.1016/j.neuropharm.2024.110239","DOIUrl":"10.1016/j.neuropharm.2024.110239","url":null,"abstract":"<div><div>Spinal cord injury (SCI) leads to severe and lasting impairments in motor and sensory functions. The intense inflammatory response following SCI is a significant challenge, and autophagy has emerged as a key factor in the recovery process. The C-C chemokine receptor type 1 (CCR1), a G-protein coupled receptor, plays a crucial role in managing the chemokine response under stress. BX471, a selective and potent CCR1 antagonist, has been explored in various disease contexts for its therapeutic potential. In this study, we assessed the effects of BX471 in a mouse model of SCI. The treatment was administered at doses of 3 and 10 mg/kg, 1 h and 6 h after the injury occurred. Results showed that BX471 significantly improved tissue structure by positively influencing autophagy and reducing inflammation. Inflammatory markers, including CCR1 ligands RANTES, MIP-1α, TNF-α, and IL-1β, were measured using Western blot analysis. Additionally, histological evaluations revealed that BX471 effectively decreased infiltration and reduced astrocyte and microglial activation, supporting the idea that enhancing autophagy through CCR1 inhibition could promote neuronal survival. The highest efficacy was observed at the 10 mg/kg dose, leading to optimal out-comes across the assessments. These findings suggest that CCR1 blockade with BX471 may offer a promising therapeutic strategy for SCI, addressing a critical gap in the current pharmacological treatment options.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"264 ","pages":"Article 110239"},"PeriodicalIF":4.6,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural modulation by nicotine aerosols and the role of flavor additives: insights from local field potentials in mice","authors":"Jingping Sun ,&nbsp;Qidong Zhang ,&nbsp;Ying Li ,&nbsp;Yunhe Zhu ,&nbsp;Nengwei Hu ,&nbsp;Junmin Wang ,&nbsp;Jian Mao ,&nbsp;Wu Fan ,&nbsp;Qingzhao Shi ,&nbsp;Guobi Chai ,&nbsp;Jianping Xie","doi":"10.1016/j.neuropharm.2024.110237","DOIUrl":"10.1016/j.neuropharm.2024.110237","url":null,"abstract":"<div><div>Research on nicotine's neurobiological effects has rarely focused on aerosols, despite their primary role in tobacco product consumption. Here, we utilized in vivo electrophysiology to examine brain activity in mice exposed to nicotine aerosols, both alone and with flavor additives (citric acid and menthol). Local field potential (LFP) recordings from the nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), and ventral posteromedial nucleus (VPM) were analyzed under saline, nicotine, nicotine with citric acid(CA + NIC), and nicotine with menthol(MENT + NIC) conditions. Nicotine exposure significantly reduced power spectral density (PSD) in the NAc-Alpha, NAc-Beta, and BLA-Beta bands, unaffected by flavor additives. Coherence between key brain regions (e.g., VPM-VTA in Beta, VPM-BLA in Alpha) also decreased with nicotine but was restored with citric acid or menthol, suggesting their role in mitigating nicotine's disruptive effects on neural synchronization. Our findings show that LFPs can effectively capture nicotine's neural effects and highlight the modulatory role of flavor additives, offering new insights into nicotine exposure management and tobacco product design.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"264 ","pages":"Article 110237"},"PeriodicalIF":4.6,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the antinociceptive effect of codeine and its peripheral but not central metabolism in adult mice","authors":"Volodya Hovhannisyan ,&nbsp;Abdel-Karim Berkati ,&nbsp;Marine Simonneaux ,&nbsp;Florian Gabel ,&nbsp;Virginie Andry ,&nbsp;Yannick Goumon","doi":"10.1016/j.neuropharm.2024.110228","DOIUrl":"10.1016/j.neuropharm.2024.110228","url":null,"abstract":"<div><div>Codeine is a natural opiate extracted from opium poppy (<em>Papaver somniferum</em>) and used to alleviate mild to moderate pain. The analgesic effect of this molecule results from its metabolism into morphine which is an agonist of the mu opioid receptor. Morphine's major metabolite morphine-3-glucuronide induces both thermal and mechanical hypersensitivies while codeine-6-glucuronide has been proposed to be antinociceptive. However, sex differences in codeine antinociceptive effect and pharmacokinetics were barely studied. To this purpose, we injected male and female mice with codeine (2.5, 5, 10, 20 and 40 mg/kg) and thermal hypersensitivity was assessed 30 min after injection using the Tail Immersion Test. Moreover, both peripheral and central metabolism of codeine were evaluated respectively in the blood or pain-related brain structures in the central nervous system. The amounts of codeine and its metabolites were quantified using the isotopic dilution method by liquid chromatography coupled to a mass spectrometer. Our results show that codeine induces a greater antinociceptive effect in males than females mice independently of the estrous cycle. Moreover, major sex differences were found in the peripheral metabolism of this molecule, with higher amounts of pronociceptive morphine-3-glucuronide and less antinociceptive codeine-6-glucuronide in females than in males. Concerning the central metabolism of codeine, we did not find significant sex differences in pain-related brain structures. Collectively, these findings support a greater codeine antinociceptive effect in males than females in mice. These sex differences could be influenced by a higher peripheral metabolism of this molecule in female mice rather than central metabolism.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"264 ","pages":"Article 110228"},"PeriodicalIF":4.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the dopamine D1 receptor in anticipatory pleasure and social play","authors":"Kate M. Witt,&nbsp;David N. Harper,&nbsp;Bart A. Ellenbroek","doi":"10.1016/j.neuropharm.2024.110225","DOIUrl":"10.1016/j.neuropharm.2024.110225","url":null,"abstract":"<div><div>Social play is a highly rewarding activity seen across mammalian species that is vital for neurobehavioural development. Dysfunctions in social play are seen across psychiatric and neurodevelopmental disorders positing the importance of understanding the neurobiological mechanisms underlying social play. A multitude of neurotransmitter systems have been implicated in social play, with the present study focused on the role of dopamine, specifically the dopamine D1 receptor. Pharmacological manipulations of dopamine and the D1 receptor reveal mixed findings. Given the limited selectivity of pharmacological tools, we explored the role of the dopamine D1 receptor in social play using dopamine D1 mutant (DAD1^−/−) rats which have a genetic reduction in functional D1 receptors. Aligning with the rewarding properties of social play, the present study also examined anticipatory behaviour for the opportunity to engage in social play. Contrary to our predictions, DAD1^−/− mutants initiated and engaged in social play similarly to wildtype controls with only subtle differences in specific elements of play behaviour. Subjects did not differ in 50 kHz vocalisations emitted during play, suggesting similar levels of consummatory pleasure. Although subjects initiated and engaged in play similarly, as predicted, DAD1^−/− mutants displayed deficits in anticipatory behaviour and pleasure for the opportunity to engage in social play. These findings support a prominent role of the D1 receptor in anticipatory behaviour, with further research needed to elucidate its role in social play.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"264 ","pages":"Article 110225"},"PeriodicalIF":4.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of genetic knockdown of the serotonin transporter on established L-DOPA-induced dyskinesia and gene expression in hemiparkinsonian rats.","authors":"Grace McManus, Ashley Galfano, Carla Budrow, Natalie Lipari, Kuei Y Tseng, Fredric P Manfredsson, Christopher Bishop","doi":"10.1016/j.neuropharm.2024.110227","DOIUrl":"10.1016/j.neuropharm.2024.110227","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder typified by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) leading to motor symptoms including resting tremor, rigidity, akinesia, and postural instability. DA replacement therapy with levodopa (L-DOPA) remains the gold-standard treatment for the motor symptoms of PD. Unfortunately, chronic use of L-DOPA leads to the development of side effects known as L-DOPA-induced dyskinesia (LID). The mechanisms underlying LID are multifaceted, but accumulating research has strongly implicated maladaptive neuroplasticity within the raphe-striatal serotonin (5-HT) circuit. The 5-HT transporter (SERT) has emerged as an intriguing therapeutic target as it is upregulated in the brains of dyskinetic patients and animal models of LID, and pharmacological blockade of SERT alters L-DOPA's effects. Therefore, the current study employed an interventional genetic knockdown of SERT (SERT-KD) to investigate its role in LID expression and LID-associated transcription factors. To do so, hemiparkinsonian, stably dyskinetic rats (N = 68) received adeno-associated virus 9 (AAV9) expressing either a short-hairpin RNA against SERT (SERT-shRNA) or a scrambled control shRNA (SCR-shRNA) after which LID reinstatement and motor performance were assayed over 2 weeks. Dorsal raphe and striatal tissue were collected for the expression analyses of known parkinsonian and LID-associated genes. Results demonstrated that SERT-KD significantly and durably reduced LID and L-DOPA-induced striatal cFOS mRNA without altering L-DOPA efficacy. Such findings point to SERT-mediated adaptations as a 5-HT mechanism by which L-DOPA exerts its actions and therapeutic target for LID.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110227"},"PeriodicalIF":4.6,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The synthetic cannabinoid agonist WIN 55,212-2 reduces experimental pruritus via CB2 receptor activation","authors":"Antonio Matt Reck ,&nbsp;David P. Siderovski ,&nbsp;Steven G. Kinsey","doi":"10.1016/j.neuropharm.2024.110216","DOIUrl":"10.1016/j.neuropharm.2024.110216","url":null,"abstract":"<div><div>Pruritus (<em>i.e.</em>, the experience that evokes a desire to scratch) is an adaptive process that can become maladaptive, leading to a persistent scratch-itch cycle that potentiates pruritus and increases the risk of infection. Cannabinoid drugs have been reported to decrease pruritus, but often at doses that also decrease locomotor activity, which confounds assessments of utility. To determine the utility of cannabinoids in treating pruritus without undesirable adverse effects, the current preclinical study investigated a range of doses of the synthetic cannabinoid agonist, WIN 55,212-2, and two minor <em>Cannabis</em> phytoconstituents, Δ⁸-tetrahydrocannabinol and β-caryophyllene, in experimentally induced pruritus in male and female C57BL/6J adult mice. WIN 55,212-2 reduced compound 48/80-induced scratching, and this antipruritic effect was prevented by either chemically blocking (via SR144528 antagonism) or genetically deleting the CB₂ cannabinoid receptor. The CB₂ receptor selective agonist, JWH-133, also attenuated compound 48/80-induced scratching, while the CB₁ positive allosteric modulator, ZCZ011, had no effect. Similarly, the minor phytocannabinoid Δ⁸-tetrahydrocannabinol reduced scratching at doses that did not affect locomotor activity. In contrast, the sesquiterpene <em>cannabis</em> constituent β-caryophyllene induced scratching, acting as a pruritogen. These preclinical data support the continuing investigation of cannabinoid receptor modulation as a potential therapeutic strategy for pruritus.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"264 ","pages":"Article 110216"},"PeriodicalIF":4.6,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}