Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options

Lafreniere, J Daniel; Kelly, Melanie E. M.

doi:10.1042/ns20170144

Cited by 12 publications

(6 citation statements)

References 231 publications

(316 reference statements)

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“…Alternatively, DAGLα inhibition may lead to accumulation of DAG. DAG can activate nonselective cation channels, including TRPV1 and TRPC3, as well as receptor- and store- operated calcium channels to activate nociceptive fibers ( Brown and Passmore, 2010 ; Lafreniere and Kelly, 2018 ; Yasko et al, 2019 ). Inhibition of DAGLα did not significantly change DAG levels in the cortex or PAG suggesting that this mechanism may not play a role in the periorbital allodynia resulting from DAGLα inhibition.…”

Section: Discussionmentioning

confidence: 99%

DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache

et al. 2021

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Recent findings suggested that Clinical Endocannabinoid Deficiency underlies the pathophysiology of pain disorders, including migraine and headache. In models of medication overuse headache induced by sustained administration of sumatriptan or morphine, 2-AG levels were selectively depleted in the periaqueductal gray (PAG) and anandamide (AEA) increased in the cortex suggesting distinct regulation of the endocannabinoid system during headache pain. These results led to the hypothesis that blockade of DAGL, to reduce 2-AG levels would induce headache-like behaviors as a new, translationally relevant model of episodic headache. Our study investigated whether non-selective and selective blockade of DAGL, the main biosynthetic enzyme for 2-AG, induced periorbital and hind-paw allodynia, photophobia, anxiety-like behaviors, responsivity to abortive anti-migraine agents, and 2-AG/AEA levels. Injection of non-selective DAGL (DH376, 10 mg/kg, IP) and selective DAGLα (LEI106, 20 mg/kg, IP) inhibitors, but not DAGLβ agents, induced facial sensitivity in 100% and ∼60% of female and male rats, respectively, without induction of peripheral sensitivity. Notably, male rats showed significantly less sensitivity than female rats after DAGLα inhibition, suggesting sexual dimorphism in this mechanism. Importantly, LEI106 induced periorbital allodynia was attenuated by administration of the clinically available abortive antimigraine agents, sumatriptan and olcegepant. Selective DAGLα inhibition induced significant photophobia as measured by the light-dark box, without anxiety like behaviors or changes in voluntary movement. Analysis of AEA and 2-AG levels at the time of peak pain sensitivity revealed reductions in 2-AG in the visual cortex and periaqueductal gray (PAG), without altering anandamide or significantly increasing diacylglycerol levels. These results provide foundational evidence for DAGL-2AG in the induction of headache-like pain and photophobia without extracephalic allodynia, thus modeling the clinical episodic migraine. Mechanistically, behavioral measures of headache sensitivity after DAGL inhibition suggests that reduced 2-AG signaling in the cortex and PAG, but not the trigeminal nucleus caudalis or trigeminal ganglia, drives headache initiation. Therefore, episodic DAGL inhibition, which reduces the time, cost, and invasiveness of currently accepted models of headache, may fill the need for episodic migraine/headache models mirroring clinical presentation. Moreover, use of this approach may provide an avenue to study the transition from episodic to chronic headache.

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Section: Discussionmentioning

confidence: 99%

DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache

et al. 2021

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“…The cornea has one of the densest concentrations of unmyelinated sensory nerve endings in the body [1,2], which are highly sensitive to mechanical stimulation, temperature, and various chemicals mediators, through receptors such as the transient receptor potential family [3]. Damage or irritation to these nerve endings resulting from ocular surface manipulations such as cataract surgery [4], long-term and improper use of contact lenses [5][6][7], and frequent exposure to irritating environmental and chemical stimuli (infection, air pollutants, hazardous chemicals, air pressure etc.)…”

Section: Introductionmentioning

confidence: 99%

Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation

et al. 2020

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Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury. We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia. Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2−/−) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation. Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2−/− mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation. CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.

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“…DAG: Diacylglycerol; DAGL: Diacylglycerol lipase; 2-AG: 2-arachidonoylglycerol; NAPE: N -acyl-phosphatidylethanolamine; NAPE-PLD: N -acyl-phosphatidylethanolamine-specific phospholipase D; TRPV1: Transient receptor potential cation channel subfamily V member 1; CB1: Cannabinoid receptor 1; CB2: Cannabinoid receptor 2; GPR55: G protein-coupled receptor 55; MAGL: Monoacylglycerol lipase; FAAH: Fatty acid amide hydrolase; EMT: Endocannabinoid membrane transporter—“?” denotes controversy surrounding the presence of said transporter. Figure used with permission from the publisher in reference [47] (version used modified by reference [48]).…”

Section: Figurementioning

confidence: 99%

Modulation of the Endocannabinoid System Following Central Nervous System Injury

Noori

Burkovskiy

Lafreniere

et al. 2019

IJMS

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Central nervous system (CNS) injury, such as stroke or trauma, is known to increase susceptibility to various infections that adversely affect patient outcomes (CNS injury-induced immunodepression—CIDS). The endocannabinoid system (ECS) has been shown to have immunoregulatory properties. Therefore, the ECS might represent a druggable target to overcome CIDS. Evidence suggests that cannabinoid type 2 receptor (CB2R) activation can be protective during the early pro-inflammatory phase after CNS injury, as it limits neuro-inflammation and, therefore, attenuates CIDS severity. In the later phase post CNS injury, CB2R inhibition is suggested as a promising pharmacologic strategy to restore immune function in order to prevent infection.

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Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options

Cited by 12 publications

References 231 publications

DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache

DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache

Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation

Modulation of the Endocannabinoid System Following Central Nervous System Injury

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