The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain

Thompson, Austen; Grenald, Shaness A.; Ciccone, Haley A.; BassiriRad, Neemah M.; Niphakis, Micah J.; Cravatt, Benjamin F.; Largent-Milnes, Tally M.; Vanderah, Todd W.

doi:10.1124/jpet.119.262337

Cited by 24 publications

(18 citation statements)

References 48 publications

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“…Both MAGL and ABHD6 degrade many monoacylglycerol species, including 2-AG [ 7 , 8 , 62 – 66 ]. MAGL and ABHD6 inhibitors have shown promise as pain therapeutics [ 61 , 66 – 71 ] and in treating neurological disorders [ 7 , 8 , 66 ], respectively. One study investigated the contribution of MAGL to NO-induced headache, but results were not obtained in both sexes [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats

et al. 2021

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Background Several chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented, but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system comprises the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands. Methods Brain tissue from naïve male and estrous staged female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unlabeled quantitative proteomic analysis, and immunohistochemistry. Results Mass spectrometry revealed significant differences in 2-AG and AEA concentrations between males and females, as well as between female estrous cycle stages. Specifically, 2-AG concentration was lower within female PAG as compared to male PAG (*p = 0.0077); female 2-AG concentration within the PAG did not demonstrate estrous stage dependence. Immunohistochemistry followed by proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG. Conclusions Our results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats

et al. 2021

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“…JWH015, a selective CB2R agonist (CB2R Ki 13.8 nM, 28-fold selectivity vs. CB1R (Showalter et al, 1996)), was purchased from Tocris (#1341, Minneapolis, MN). MJN110 and JWH015 were dissolved in a vehicle solution consisting of 10% dimethyl sulfoxide, 10% Tween-80, and 80% saline for injection (1 ml/kg, i. p.) with dosages of 5 and 3 mg/kg, respectively, based on the previous studies (Niphakis et al, 2013;Grenald et al, 2017;Thompson et al, 2020). Morphine sulfate was obtained from the NIDA Drug Supply program and was dissolved in saline for injection (1 ml/kg).…”

Section: Drug Treatmentmentioning

confidence: 99%

The Effects of Repeated Morphine Treatment on the Endogenous Cannabinoid System in the Ventral Tegmental Area

et al. 2021

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The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry. Studies here using proteomic analysis and quantitative real-time PCR (qRT-PCR) found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; three of these proteins or genes (PLCγ2, ABHD6, and CB2R) were significantly affected after repeated morphine exposure (CB2R was only detected by qRT-PCR but not proteomics). We also identified that repeated morphine treatment does not alter either anandamide (AEA) or 2-arachidonoylglycerol (2-AG) levels in the VTA compared to saline treatment; however, there may be diminished levels of anandamide (AEA) production in the VTA 4 h after a single morphine injection in both chronic saline and morphine pretreated cohorts. Treating the animals with an inhibitor of 2-AG degradation significantly decreased repeated opioid rewarding behavior. Taken together, our studies reveal a potential influence of sustained opioids on the endocannabinoid system in the VTA, suggesting that the endogenous cannabinoid system may participate in the opioid-induced reward.

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“…Thus, in addition to the ongoing challenge of developing new therapeutics capable of treating the underlying cancer, there is also an urgent unmet clinical need to develop new therapies, which provide cancer patients with palliative care to relieve pain and improve quality of life. Notably, endocannabinoid has been shown to alleviate murine bone cancer pain without producing the side effects of opioids 11 . An ideal therapeutic approach would be one that is capable of actively treating the underlying cancer while concurrently suppressing cancer-associated pain, thereby treating the pain and the underlying disease.…”

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confidence: 99%

STING suppresses bone cancer pain via immune and neuronal modulation

et al. 2021

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Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.

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The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain

Cited by 24 publications

References 48 publications

Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats

Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats

The Effects of Repeated Morphine Treatment on the Endogenous Cannabinoid System in the Ventral Tegmental Area

STING suppresses bone cancer pain via immune and neuronal modulation

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