Chronic administration of cannabinoid agonists ACEA (CB1), AM1241 (CB2), and CP55,940 (mixed CB1/CB2) induce sex-specific differences in tolerance and sex hormone changes in a chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term anti-allodynic efficacy of CB1-selective (ACEA), CB2-selective (AM1241), and CB1/CB2 mixed (CP55,940) agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to anti-allodynic effects, with females developing tolerance more rapidly than males, while the anti-allodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. Significance Statement CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB¬2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB¬2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB¬2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.

Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3-100 mg/kg), or AT (0.1-30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30-100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5-100 mg/kg in males and 10-100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. SIGNIFICANCE STATEMENT: Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.

Mechanisms of cannabinoid tolerance.

Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance and the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB1R) that are responsible tolerance. CB1R expression is downregulated in tolerant animals and humans while there is strong evidence of CB1R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB1R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB1R desensitization and downregulation including the action of G protein-coupled receptor kinases, ß-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB1R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.

Contingency Management and SARS-CoV-2 Testing Among People Who Inject Drugs.

OBJECTIVES: People who inject drugs (PWID) are especially vulnerable to morbidity and mortality as a result of SARS-CoV-2 infection because of social and physical health vulnerabilities. Routine testing for SARS-CoV-2 is critical to reduce transmission. Contingency management-the provision of tangible rewards to reinforce positive behavior-can promote the use of health services among PWID. Evidence is scarce on the utility of contingency management to promote SARS-CoV-2 testing. The objective of this study was to evaluate the effectiveness of contingency management to increase testing among PWID. METHODS: SARS-CoV-2 testing was implemented at 9 syringe exchange program sites in partnership with an Oregon-based nonprofit organization for 5 weeks without contingency management and for 6 weeks with contingency management (a $10 financial incentive for testing) from February 1 through mid-April 2021. We measured rates of testing among syringe exchange program clients before and after implementation of contingency management. RESULTS: Before contingency management, SARS-CoV-2 testing occurred during approximately 131 of 1410 (9.3%) client encounters, and 123 of 997 (12.3%) unique clients were tested. During contingency management, testing occurred during approximately 571 of 1756 (32.5%) client encounters, and 407 of 1151 (35.4%) unique clients were tested. Rates of testing increased from 0.04 (SD, 0.04) before contingency management implementation to 0.25 (SD, 0.15) after implementation (t8 = -3.88; P = .005; Cohen d = 1.46). CONCLUSIONS: Contingency management facilitated uptake of SARS-CoV-2 testing among PWID. Contingency management may be an effective strategy for improving communicable disease testing beyond testing for SARS-CoV-2 and for improving vaccine uptake among PWID and warrants additional research.

Sex differences and the endocannabinoid system in pain.

Cannabis use has been increasing in recent years, particularly among women, and one of the most common uses of cannabis for medical purposes is pain relief. Pain conditions and response to analgesics have been demonstrated to be influenced by sex, and evidence is emerging that this is also true with cannabinoid-mediated analgesia. In this review we evaluate the preclinical evidence supporting sex differences in cannabinoid pharmacology, as well as emerging evidence from human studies, both clinical and observational. Numerous animal studies have reported sex differences in the antinociceptive response to natural and synthetic cannabinoids that may correlate to sex differences in expression, and function, of endocannabinoid system components. Female rodents have generally been found to be more sensitive to the effects of Δ9-THC. This finding is likely a function of both pharmacokinetic and pharmacodynamics factors including differences in metabolism, differences in cannabinoid receptor expression, and influence of ovarian hormones including estradiol and progesterone. Preclinical evidence supporting direct interactions between sex hormones and the endocannabinoid system may translate to sex differences in response to cannabis and cannabinoid use in men and women. Further research into the role of sex in endocannabinoid system function is critical as we gain a deeper understanding of the impact of the endocannabinoid system in various disease states, including chronic pain.

Group B streptococcus toxic shock-like syndrome in a healthy woman: a case report.

BACKGROUND: Toxic shock syndrome (TSS) is caused by Staphylococcus aureus infection. The disease entity manifests clinically as fever, hypotension, diffuse macular erythema that progresses to desquamation, and dysfunction of > 3 organ systems. Toxic shock-like syndrome (TSLS) has the same clinical manifestation as TSS but is caused by Streptococcus, usually group A, C or G. Here we report on a healthy woman who experienced group B Streptococcus (GBS)-related TSLS, possibly related to tampon use. CASE: A 37-year-old woman, gravida 1, para 1, met the diagnostic criteria for TSS/TSLS 5 days after her last tampon use. Blood, urine and vaginal cultures were positive only for GBS. Analysis of the blood isolate suggested a novel GBS superantigen. CONCLUSION: This is the second reported case of GBS causing tampon-associated TSS/TSLS. Up to 40% of healthy menstruating women are vaginally colonized with GBS. Superantigens elaborated by staphylococci and streptococci induce an immunologic mediator storm that affects the circulatory and end-organ systems to produce the clinical picture. Prompt medical therapy involves large-volume isotonic fluid resuscitation and antibiotic coverage with vancomycin and an antistaphylococcal beta-lactam. Clindamycin may dampen the immunologic response and endotoxin production. Corticosteroids and intravenous immunoglobulin may be useful adjuncts; however, nonsteroidal antiinflammatories should be avoided.