Untapped endocannabinoid pharmacological targets: Pipe dream or pipeline?

Wilkerson, Jenny L.; Bilbrey, Joshua A.; Felix, Jasmine S.; Makriyannis, Alexandros; McMahon, Lance Richard

doi:10.1016/j.pbb.2021.173192

Cited by 11 publications

(11 citation statements)

References 368 publications

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“…Favorable preclinical results, which showed decreased trafficking of pain transmission, were clinically confirmed in migraine patients. In the field of NP, only a few clinical studies are available [24].…”

Section: Of 29mentioning

confidence: 99%

“…Moreover, the system involves enzymes that regulate the synthesis and degradation of the ligands. CBR-1 is located in the nervous systemmainly in the brain, while CBR-2 is found in immune system [24].…”

Section: Migrainementioning

confidence: 99%

“…Other enzymes of this system include monoacylglycerol lipase (MAGL), diacylglycerol lipase alpha, diacylglycerol lipase beta and alpha/beta hydrolase domain 6. Fatty acid ethanolamides, together with 2-AG, are the main endocannabinoid signaling lipids interacting with CBR-1 and CBR-2 [24,162]. The endocannabinoid system seems to be dysfunctional and dysregulated in migraine.…”

Section: Migrainementioning

confidence: 99%

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Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain

Tajti¹,

Delia²,

Csáti³

et al. 2023

Preprint

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Migraine and neuropathic pain (NP) are evocative of painful, disabling, chronic conditions which exhibit resembling symptoms and thus considered to share a common etiology. Calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant search for more effective therapeutic targets for pain management. This scoping review overviews human studies of common pathogenic factors in migraine and NP to explore potential novel therapeutic targets. CGRP causes inflammation in the meninges; monoclonal antibodies and inhibitors target CGRP. Gluta-mate-induced hyperexcitability and subsequent sensitization are closely linked to an alteration of the tryptophan (Trp)-kynurenine (KYN) metabolic system; the Trp-KYN system may serve as a potential target. Microglial overaction is observed in migraine and NP; modifying the microglial activity may be a possible approach. Cytokine-induced inflammation is a leading hypothesis of the pathogenesis of the conditions; alleviating neuroinflammation may complement a pain-relieving armamentarium. Transient receptor potential (TRP) ion channels evoke the release of several substances; TRP ion channels may potentially emerge as new targets. The endocannabinoid system plays a major role in the pain trafficking pathway; modification of the system may open a new path toward discovery of new analgesics. Here we highlight the mechanism of those common pathogenic factors to explore therapeutic targets for innovative pain management in migraine and NP.

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Section: Of 29mentioning

confidence: 99%

Section: Migrainementioning

confidence: 99%

Section: Migrainementioning

confidence: 99%

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Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain

Tajti¹,

Delia²,

Csáti³

et al. 2023

Preprint

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“…Other eCBs exist, such as the N-palmitoylethanolamide (PEA) [159], which has several anti-inflammatory and neuroprotective properties [160][161][162], and its effects can be mediated, for example, by activation of CB2, TRPV1, and PPARα [157,159]. eCBs are synthesized by several cells and act on different brain cells, including neurons and microglia [163,164]. Therefore, the widespread localization of the eCB system molecules in brain cells and its multi-target actions allows the control of many functions, from controlling local cellular actions to big circuits involved in behavior.…”

Section: The Ecb System In Neuroimmune and Behavioral Response To Str...mentioning

confidence: 99%

“…Additional to CB1Rs/CB2Rs, behavioral, neuroprotective, and anti-inflammatory effects of eCBs in stress situations can be further mediated by nuclear PPARs, mainly PPARα and PPARγ [164]; the last one has the highest expression levels in the CNS, in different cell types [184]. PPARs act as transcription factors by binding to specific DNA regions and regulating gene expression [165].…”

Section: The Ecb System In Neuroimmune and Behavioral Response To Str...mentioning

confidence: 99%

Toll-like receptor 4 in the interface between neuroimmune response and behavioral alterations caused by stress

Souza-Junior

Cunha

Lisboa

2022

Explor Neuroprot Ther

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Different stressors can elicit neuroinflammatory responses modulated by innate immunity receptors, such as the family of Toll-like receptors (TLRs). The TLR4, a pattern recognition receptor (PRR), is involved in many diseases, such as inflammatory and central nervous system (CNS) diseases. Stress exposure can regulate the expression of PRRs, including TLR4, in the brain of animals, especially in the hippocampus and prefrontal cortex. Moreover, TLR4 modulates behavior and neuroinflammatory responses in the brain. In addition, to TLR4, the endocannabinoid (eCB) system plays a role in stress response and immunity, acting as a regulatory, stress-buffer system. This system is involved in many TLRs-mediated immune responses, such as microglia activation. Therefore, pharmacological approaches targeting the eCB system could modulate neuroinflammatory responses to stress by interfering with the TLR4 pathway. Although the connection between TLR4, stress, and neuroinflammation is well documented, almost no pre-clinical studies investigate the possible direct relationship between TLR4, behavior, stress, and the eCB system. Studies exploring the relationship between stress, neuroinflammation, TLR4, and the eCB system were searched using Pubmed, Web of Science, and Embase databases. Based on this search, this review is focused on the involvement of TLR4 receptors and signaling in neuroinflammation and the behavioral consequences of stress exposure. Moreover, evidence of the eCB system modulating TLR4-mediated responses was brought to the attention, pointing out a possible regulatory role of these responses by eCBs in behavior changes related to mood disorders.

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