ThePineapple - Journal Club #51: Mechoulam | Male Infertility | Sex | Fentanyl

Journal Club #51: Mechoulam, Male Infertility, Sex, Fentanyl

Week of 07-24-22

When we select our papers for the journal club we tend to largely avoid “review” articles in favor of new data, be it pre-clinical research articles, clinical trials or the odd meta-analysis. But every now and then a review is released that you just shouldn’t ignore. This week is one of those times when the most noteworthy article that we are posting is actually a narrative review. The reason it is noteworthy is because the review was written by Prof. Raphael Mechoulam, largely credited with being the “grandfather of cannabis science”. Mechoulam and his research group were first to isolate and characterize the psychoactive THC many decades ago. Many of the major contributions in the field of cannabinoids and also the human endocannabinoid system are directly derived from either his lab or his students who continued to follow in his footsteps. Obviously, if you are one of the budding cannabis scientists, you likely already know this, if not—then you really should! A good place to start would be our article on the “Entourage Effect”. 

Note: This is a post for cannabis scientists. A weekly curation of fresh papers that help advance our understanding of cannabis and the endocannabinoid system.

A Delightful Trip Along the Pathway of Cannabinoid and Endocannabinoid Chemistry and Pharmacology.

Mechoulam R. 

Annu Rev Pharmacol Toxicol. 2022 Jul 18.

After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65 year, I have worked on the chemistry and pharmacology of natural products. During the last few decades, most of my research has been on plant cannabinoids, the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, and endogenous anandamide-like compounds, all of which are involved in a wide spectrum of physiological reactions. Two plant cannabinoids, Δ9-tetrahydrocannabinol and cannabidiol, are approved drugs. However, the endogenous cannabinoids and the anandamide-like constituents have not yet been well investigated in humans. For me, intellectual freedom-the ability to do research based on my own scientific interests-has been the most satisfying part of my working life. Looking back over the 91 years of my long life, I conclude that I have been lucky, very lucky, both personally and scientifically. 

doi: 10.1146/annurev-pharmtox-051921-083709. Epub ahead of print. PMID: 35850522.

Effects of recreational cannabis on testicular function in primary infertile men.

Belladelli F, Fallara G, Pozzi E, Corsini C, Cilio S, Raffo M, d'Arma A, Boeri L, Capogrosso P, Eisenberg M, Montorsi F, Salonia A. 

Andrology. 2022 Jul 22. 

Male factor contributes to up to 50% of cases of couples experiencing infertility. Cannabis is one of the most commonly used recreational drugs and its effects on the reproductive system have been largely debated in the literature. The aim of this study is to evaluate the effect of recreational cannabis use on total T (tT) levels, gonadal status, and sperm parameters in a cohort of primary infertile non-Finnish, white-European men. Data of 2074 white-European men visited for primary couple's infertility were analyzed. Lifestyle factors and cannabis use were investigated in all participants. Semen analyses were based on the 2010 WHO reference criteria. Serum hormones were evaluated, and patients were subdivided based on their gonadal status. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Descriptive statistics and linear regression analyses were used to test the association between cannabis use, sperm parameters, and hormonal levels. Logistic regression analyses tested potential predictors for abnormal sperm parameters and gonadal status. Of 2074, 225 (10.9%) patients reported cannabis use in their lifetime. Total Testosterone levels were lower in cannabis users compared to non-users (p = 0.03). In a multivariable linear regression analysis, cannabis use was inversely associated with tT levels (ß = -0.372 ng/mL; p = 0.005) but not with FSH nor with LH levels. Conversely, at multivariable logistic regression model cannabis use was not associated with the type of hypogonadism. At multivariable linear regression analysis, cannabis use was inversely associated with sperm morphology (p = 0.007), while not with both sperm concentration and sperm motility. Similarly, at adjusted logistic regression analysis cannabis use resulted associated with teratozoospermia (p = 0.039), but not with oligo-, astheno- and azoospermia. Infertile men using cannabis are at higher risk of having lower testosterone levels and altered sperm morphology as compared with non-users. This article is protected by copyright. All rights reserved.

doi: 10.1111/andr.13235. Epub ahead of print. PMID: 35868833.

Sex-specific cannabinoid 1 receptors on GABAergic neurons in the ventrolateral periaqueductal gray mediate analgesia in mice. 

Jiang Z, Wang Q, Zhao J, Wang J, Li Y, Dai W, Zhang X, Fang Z, Hou W, Xiong L. 

J Comp Neurol. 2022 Sep;530(13):2315-2334. 

Sex differences in analgesic effects have gradually attracted public attention in preclinical and clinical studies. Both human and animal females are more sensitive to cannabinoid antinociception than males. Expression of the cannabinoid 1 receptor (CB1 R) and the function of the endocannabinoid system have been explored in both male and female mice and CB1 Rs in the ventrolateral periaqueductal gray (vlPAG) participate in antinociception. However, whether there are cell-type- and sex-specific patterns of vlPAG CB1 R expression that affect analgesia is unknown. In the current study, we either activated or inhibited CB1 Rs in the vlPAG and found that female mice produced stronger analgesia or developed more robust mechanical allodynia than males did. Specific deletion of GABAergic CB1 Rs in the vlPAG promoted stronger mechanical allodynia in female mice than that in male mice. However, no sex differences in cannabinoid antinociception were found following chemogenetic inhibition of GABAergic neurons. Using fluorescence in situ hybridization, we found that the sex difference in cannabinoid antinociception was due to females having higher expression of GABAergic CB1 Rs in the vlPAG than males. Furthermore, activation of CB1 Rs in the vlPAG significantly reduced the frequency of GABA-mediated spontaneous inhibitory postsynaptic currents recorded in vGlut2-tdTomato positive neurons in both sexes. This effect was greater in females than males and this reduction was closely related to CB1 R expression difference between sexes. Our work indicates that vlPAG GABAergic CB1 Rs modulate cannabinoid-mediated analgesia in a sex-specific manner, which may provide a potential explanation of sex difference found in the analgesic effect of cannabinoids.

doi: 10.1002/cne.25334. Epub 2022 Jun 18. PMID: 35716006.

Lack of Causal Roles of Cannabinoid and Dopamine Neurotransmitter Systems in Orbitofrontal and Piriform Cortex in Fentanyl Relapse in Rats. 

Claypool SM, Behdin S, Applebey SV, Orihuel J, Ma Z, Reiner DJ. 

eNeuro. 2022 Jul 20;9(4):ENEURO.0496-21.2022. 

The orbitofrontal cortex (OFC) and piriform cortex (Pir) play a role in fentanyl relapse after food choice-induced voluntary abstinence, a procedure mimicking abstinence because of availability of alternative nondrug rewards. We used in situ hybridization and pharmacology to determine the role of OFC and Pir cannabinoid and dopamine receptors in fentanyl relapse. We trained male and female rats to self-administer food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 d (6 h/d). We assessed fentanyl relapse after 12 discrete choice sessions between fentanyl and food (20 trials/d), in which rats voluntarily reduced fentanyl self-administration. We used RNAscope to determine whether fentanyl relapse is associated with activity (indicated by Fos) in OFC and Pir cells expressing Cnr1 [which encodes cannabinoid 1 (CB1) receptors] or Drd1 and Drd2 (which encode dopamine D1 and D2 receptors). We injected a CB1 receptor antagonist or agonist (0.3 or 1.0 µg AM251 or WIN55,212-2/hemisphere) into OFC or a dopamine D1 receptor antagonist (1.0 or 3.0 µg SCH39166/hemisphere) into Pir to determine the effect on fentanyl relapse. Fentanyl relapse was associated with OFC cells co-expressing Fos and Cnr1 and Pir cells co-expressing Fos and Drd1 However, injections of the CB1 receptor antagonist AM251 or agonist WIN55,212-2 into OFC or the dopamine D1 receptor antagonist SCH39166 into Pir had no effect on fentanyl relapse. Fentanyl relapse is associated with activation of Cnr1-expressing OFC cells and Drd1-expressing Pir cells, but pharmacological manipulations do not support causal roles of OFC CB1 receptors or Pir dopamine D1 receptors in fentanyl relapse.

doi: 10.1523/ENEURO.0496-21.2022. PMID: 35768212.