Sex-specific mechanisms of tolerance for the cannabinoid agonists CP55,940 and delta-9-tetrahydrocannabinol (Δ9-THC)

Henderson-Redmond, Angela N.; Sepulveda, Diana E.; Ferguson, Erin L.; Kline, Aaron M.; Piscura, Mary K; Morgan, Daniel J.

doi:10.1007/s00213-021-05886-9

Cited by 8 publications

(13 citation statements)

References 74 publications

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“…Wakley et al, 2014a;LaFleur et al, 2018;Henderson-Redmond et al, 2022). In the present study, acute THC at various doses (1, 3, and/or 10 mg/kg) were found to have profound antinociceptive effects independent of sex.…”

supporting

confidence: 48%

Effects of acute Δ9 -tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Yadav-Samudrala

Gorman

Dodson

et al. 2022

Preprint

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Cannabis use is highly prevalent especially among people living with HIV (PLWH). Activation of the anti-inflammatory and neuroprotective endocannabinoid system by phytocannabinoids, i.e. Δ9-tetrahydrocannabinol (THC), has been proposed to reduce HIV symptoms. However, THC’s effects on HIV-associated cognitive impairments are unclear. Using HIV-1 Tat transgenic mice, the current study investigates acute THC effects on various behavioral outcomes and the endocannabinoid system. Minor or no effects of THC doses (1, 3, 10 mg/kg) were noted for body mass, body temperature, locomotor activity, and coordination, but spontaneous nociception was significantly decreased, with Tat induction increasing antinociceptive THC effects. Anxiogenic effects of THC (10 mg/kg) were demonstrated in Tat(−) females and males compared to vehicle-treated mice, with overall increased anxiety-like behavior in females compared to males. Object recognition memory was diminished by acute THC (10 mg/kg) injections in Tat(−) but not Tat(+) females, without affecting males. For the endocannabinoid system and related lipids, no effects were noted for acute THC, but female sex and Tat induction was associated with elevated 2-AG, AEA, AA, CB1R, CB2R, FAAH and/or MAGL expression in various CNS regions. Further, females demonstrated higher AEA levels compared to males in most CNS structures, and AEA levels in the prefrontal cortex of Tat(+) females were negatively associated with recognition memory. Overall, findings indicate that acute THC exposure exerts differential effects on behavior in the context of neuroHIV dependent on sex, potentially due to an altered endocannabinoid system, which may be of relevance in view of potential cannabis-based treatment options for PLWH.

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supporting

confidence: 48%

Effects of acute Δ9 -tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Yadav-Samudrala

Gorman

Dodson

et al. 2022

Preprint

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“…The current study aimed to not only measure catalepsy alongside other measures of the tetrad, but utilize a full CB1R agonist and a clinically relevant DORA in both male and female mice. Compared to the CB1R partial agonist Δ 9 -THC, which was used by Flores et al (2016) , CP55,940 is a full agonist of CB1R ( Howlett and Abood, 2017 ) that is well-documented to produce more potent and efficacious responses in vitro and in vivo ( Patel et al, 2020 ; Zagzoog et al, 2020 ; Henderson-Redmond et al, 2021 ). In the current study, CP55,940 (0.1–10 mg/kg) produced similar dose-dependent sedative effects in both males and females.…”

Section: Discussionmentioning

confidence: 99%

In vivo Evidence for Brain Region-Specific Molecular Interactions Between Cannabinoid and Orexin Receptors

et al. 2021

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The endocannabinoid and orexin neuromodulatory systems serve key roles in many of the same biological functions such as sleep, appetite, pain processing, and emotional behaviors related to reward. The type 1 cannabinoid receptor (CB1R) and both subtypes of the orexin receptor, orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R) are not only expressed in the same brain regions modulating these functions, but physically interact as heterodimers in recombinant and neuronal cell cultures. In the current study, male and female C57BL/6 mice were co-treated with the cannabinoid receptor agonist CP55,940 and either the OX2R antagonist TCS-OX2-29 or the dual orexin receptor antagonist (DORA) TCS-1102. Mice were then evaluated for catalepsy, body temperature, thermal anti-nociception, and locomotion, after which their brains were collected for receptor colocalization analysis. Combined treatment with the DORA TCS-1102 and CP55,940 potentiated catalepsy more than CP55,940 alone, but this effect was not observed for changes in body temperature, nociception, locomotion, or via selective OX2R antagonism. Co-treatment with CP55,940 and TCS-1102 also led to increased CB1R-OX1R colocalization in the ventral striatum. This was not seen following co-treatment with TCS-OX2-29, nor in CB1R-OX2R colocalization. The magnitude of effects following co-treatment with CP55,940 and either the DORA or OX2R-selective antagonist was greater in males than females. These data show that CB1R-OX1R colocalization in the ventral striatum underlies cataleptic additivity between CP55,940 and the DORA TCS-1102. Moreover, cannabinoid-orexin receptor interactions are sex-specific with regards to brain region and functionality. Physical or molecular interactions between these two systems may provide valuable insight into drug-drug interactions between cannabinoid and orexin drugs for the treatment of insomnia, pain, and other disorders.

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“…Both delta-9-tetrahydrocannabinol (Δ 9 -THC), the primary psychoactive phytocannabinoid in cannabis, and CP55,940, a potent synthetic cannabinoid, have documented "tetrad" effects, including hypolocomotion, hypothermia, catalepsy, and analgesia (Gilbert et al, 2016;Janoyan et al, 2002;Moore & Weerts, 2022). Preclinical research in rodents demonstrates rapid tolerance to the antinociceptive and hypothermic effects of both agonists and lower potency and efficacy for Δ 9 -THC compared to CP55,940 (Henderson-Redmond et al, 2020;Henderson-Redmond et al, 2022;LaFleur et al, 2018b). In addition to differences in full versus partial agonism between Δ 9 -THC (partial agonist) and CP55,940 (full agonist), divergence in response to these compounds could be due to functional selectivity as CB1R activation by Δ 9 -THC, CP55,940, and other cannabinoid agonists can differentially stimulate ERK ½, JNK, and p38 MAPK pathways (Daigle, Kearn, et al, 2008;Derkinderen et al, 2001;Henderson-Redmond et al, 2020;Ibsen et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Mutant S426A/S430A mice, possessing serine to alanine point mutations, are resistant to cannabinoid-induced desensitization and display delayed tolerance development to the antinociceptive and hypothermic effects of cannabinoid agonists (Henderson-Redmond et al, 2020;Henderson-Redmond et al, 2022;Morgan et al, 2014;Nealon et al, 2019). Similarly, β-arrestin2 (-/-) knockout mice exhibit a similar decrease in cannabinoid tolerance and CB1R desensitization (Breivogel et al, 2008;Nguyen et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Dose-response curves were also generated in mice that were administered 30 mg/kg of Δ 9 -THC once-daily for 7 or 0.6 mg/kg of CP55,940 once-daily for 14 consecutive days. These doses were selected based on previously published work from our laboratory where both male and female mice exhibited antinociceptive tolerance to 30 mg/kg of Δ 9 -THC after 7 days (Henderson-Redmond et al, 2022;Morgan et al, 2014) and to 0.6 mg/kg of CP55,940 after more than 12 days (Henderson-Redmond et al, 2022) of once-daily injections. In addition to our previously published regimen, dosing regimens of twice-daily Δ 9 -THC (10 mg/kg) for 6.5 days was enough to show significant decrease in antinociception and hypothermia and decreased GTPγS binding in the PAG, which mediates antinociception (McKinney et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Cannabinoid Tolerance in S426A/S430A xβ-Arrestin 2 Knockout Double-Mutant Mice

Piscura

Sepulveda

Maulik

et al. 2023

J Pharmacol Exp Ther

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Tolerance to compounds that target G protein-coupled receptors (GPCR), such as the cannabinoid type-1 receptor (CB1R), is in part facilitated by receptor desensitization. Processes that mediate CB1R desensitization include phosphorylation of CB1R residues S426 and S430 by a GPCR kinase (GRK), and subsequent recruitment of the β-arrestin2 scaffolding protein.Tolerance to cannabinoid drugs is reduced in S426A/S430A mutant mice and β-arrestin2 knock out (KO) mice according to previous work in vivo. However, the presence of additional phosphorylatable residues on the CB1R C-terminus made it unclear as to whether recruitment to S426 and S430 accounted for all desensitization and tolerance by β-arrestin2. Therefore, we assessed acute response and tolerance to the cannabinoids, delta-9-tetrahydrocannabinol (Δ 9 -THC) and CP55,940, in S426A/S430A x β-arrestin2 KO double mutant mice. We observed both delayed tolerance and increased sensitivity to the antinociceptive and hypothermic effects of CP55,940 in male S426A/S430A single and double mutant mice compared to wild-type littermates, but not with Δ 9 -THC. Female S426A/S430A single and double mutant mice were more sensitive to acute antinociception (CP55,940 and Δ 9 -THC) and hypothermia (CP55,940 only) exclusively after chronic dosing, and did not differ in the development of tolerance. These results indicate that phosphorylation of S426 and S430 are likely responsible for β-arrestin2mediated desensitization, as double mutant mice did not differ from the S426A/S430A single mutant model in respect to cannabinoid tolerance and sensitivity. We also found antinociceptive and hypothermic effects from cannabinoid treatment demonstrate sex-, agonist-, and durationdependent features.

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Sex-specific mechanisms of tolerance for the cannabinoid agonists CP55,940 and delta-9-tetrahydrocannabinol (Δ9-THC)

Cited by 8 publications

References 74 publications

Effects of acute Δ9 -tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Effects of acute Δ9 -tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

In vivo Evidence for Brain Region-Specific Molecular Interactions Between Cannabinoid and Orexin Receptors

Cannabinoid Tolerance in S426A/S430A xβ-Arrestin 2 Knockout Double-Mutant Mice

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