Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55

Guerrero-Alba, Raquel; Barragán-Iglesias, Paulino; González‐Hernández, Abimael; Valdez-Moráles, Eduardo E.; Granados‐Soto, Vinicio; Condés‐Lara, Miguel; Rodriguez, Martín Gerardo; Marichal‐Cancino, Bruno A.

doi:10.3389/fphar.2018.01496

Cited by 77 publications

(57 citation statements)

References 262 publications

(300 reference statements)

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“…The vasopressor responses to either electrical stimulation or noradrenaline were significant when compared with their corresponding baseline values (not shown). The electrically induced vasopressor responses are induced by selective sympathetic stimulation, as only negligible changes in heart rate were observed, as previously reported by our group [5,29,31]. Figure 1 shows the vasopressor responses induced by electrical stimulation before (control) and during the i.v.…”

Section: Initial Effects Produced By Electrical Sympathetic Stimulatisupporting

confidence: 79%

“…Endogenous cannabinoids and related mediators (i.e., endocannabinoids and endocannabinoid-like compounds) play a role in the modulation of a wide variety of physiological functions with potential therapeutic use [1][2][3][4][5][6][7]. In cardiovascular homeostasis, they exert actions on systemic blood pressure and local blood flow by mechanisms partially elucidated, including: (i) autonomic and sensory neural modulation [8,9]; (ii) stimulation of endothelial nitric oxide [10]; and (iii) control of smooth muscle cell activity [11].…”

Section: Introductionmentioning

confidence: 99%

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Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats

et al. 2020

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Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB 1 , CB 2 , TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequencyand dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB 1 ), AM630 (CB 2 ), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoylethanolamide (0.1-3.1 μg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 μg/kg NIDA41020, 100 μg/kg capsazepine, or 31 μg/kg cannabidiol; (ii) unaffected by 310 μg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 μg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB 1 , TRPV1 and probably GPR55, but not by CB 2 , receptors.

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Section: Initial Effects Produced By Electrical Sympathetic Stimulatisupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats

et al. 2020

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“…CB1R was first discovered as the receptor for 9-tetrahydrocannabinol (THC), the major psychoactive ingredient in Cannabis sativa (158). Peripherally, CB1R is primarily expressed by neurons within the heart, small intestine, urinary bladder and vas deferens, while centrally CB1R is expressed at the highest concentrations by neurons in the cerebellum, hippocampus, basal ganglia and cerebral cortex (157,159,160). Clinical application of CB1R agonists are limited by development of tolerance, psychotropic effects (e.g., cognitive impairment, catalepsy, and negative impacts on learning and memory), and risk of hypothermia (157).…”

Section: Cannabinoid Receptorsmentioning

confidence: 99%

“…CB2R is abundantly expressed by peripheral immune cells (e.g., lymphocytes, neutrophils, and macrophages), and at lower levels within the CNS primarily on microglia, but has also been identified on some neurons (e.g., in the hippocampus, cortex, and substantia nigra) (159)(160)(161)(162)(163). CB 2 R signaling, while less well-understood, appears to primarily promote anti-inflammatory effects (164), and lack the unwanted psychotropic effects observed with CB1R activation (132).…”

Section: Cannabinoid Receptorsmentioning

confidence: 99%

Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

2019

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Current pain therapeutics offer inadequate relief to patients with chronic pain. A growing literature supports that pro-inflammatory cytokine signaling between immune, glial, and neural cells is integral to the development of pathological pain. Modulation of these communications may hold the key to improved pain management. In this review we first offer an overview of the relationships between pro-inflammatory cytokine and chemokine signaling and pathological pain, with a focus on the actions of cytokines and chemokines in communication between glia (astrocytes and microglia), immune cells (macrophages and T cells), and neurons. These interactions will be discussed in relation to both peripheral and central nervous system locations. Several novel non-neuronal drug targets for controlling pain are emerging as highly promising, including non-viral IL-10 gene therapy, which offer the potential for substantial pain relief through localized modulation of targeted cytokine pathways. Preclinical investigation of the mechanisms underlying the success of IL-10 gene therapy revealed the unexpected discovery of the powerful anti-nociceptive anti-inflammatory properties of D-mannose, an adjuvant in the non-viral gene therapeutic formulation. This review will include gene therapeutic approaches showing the most promise in controlling pro-inflammatory signaling via increased expression of anti-inflammatory cytokines like interleukin-10 (IL-10) or IL-4, or by directly limiting the bioavailability of specific pro-inflammatory cytokines, as with tumor necrosis factor (TNF) by the TNF soluble receptor (TNFSR). Approaches that increase endogenous anti-inflammatory signaling may offer additional opportunities for pain therapeutic development in patients not candidates for gene therapy. Promising novel avenues discussed here include the disruption of lymphocyte function-associated antigen (LFA-1) activity, antagonism at the cannabinoid 2 receptor (CB2R), and toll-like receptor 4 (TLR4) antagonism. Given the partial efficacy of current drugs, new strategies to manipulate neuroimmune and cytokine interactions hold considerable promise.

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“…These pain states include measures of acute analgesia, as well as neuropathic, inflammatory, and cancer pain modalities (Elikottil et al, 2009;Xiong et al 2011;Rock et al, 2019). Likewise, a large number of receptor systems have been implicated in mediating cannabinoid analgesia, including the cannabinoid receptors themselves (Mulpuri et al, 2018;Li et al 2019;Grenald et al, 2017), TRP channels (Muller et al, 2019), G protein-coupled receptors (Rodríguez-Muñoz et al, 2018;Guerrero-Alba et al, 2019), and glycine receptors (Xiong et al, 2011(Xiong et al, , 2012. While many of these studies have focused on acute outcomes of only one or several drug administrations, long-term studies of cannabinoids in humans have shown mixed, and often subtle effects in treatment of pain (Vučković et al, 2018;Lötsch et al, 2018), suggesting that acute pain models may be inadequate when considering chronic pain.…”

Section: Introductionmentioning

confidence: 99%

Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain

Leung¹,

Abraham²,

Wong³

et al. 2019

Preprint

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AcknowledgmentsWe thank the Mass Spectrometry facility at the University of Washington for serum processing. AbstractChronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed animals to consume D9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Animals stably consumed these gelatins over 3 weeks, with detectable serum levels. We designed a real-time gelatin measurement system, and observed that mice consumed gelatin throughout the light and dark cycles, with THC-gelatin animals consuming less than the other groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after one week while THC or CBD reduced allodynia over three weeks. Hyperalgesia took longer to develop after sciatic nerve injury, but by the last day of testing THC significantly reduced hyperalgesia responses, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by both THC and CBD. This study demonstrates that mice will voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids can provide long-term relief of chronic pain states.Additionally, ultrasonic clicks may objectively represent the pain status of a mouse and could be integrated into future pain models.

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Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55

Cited by 77 publications

References 262 publications

Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats

Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats

Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain

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