Endocannabinoids in TNF-α and Ethanol Actions

Rettori, Valéria; Fernández‐Solari, Javier; Prestifilippo, Juan Pablo; Mohn, Claudia; Laurentiis, Andrea De; Bornstein, Stefan R.; Ehrhart‐Bornstein, Monika; Elverdín, Juan C.; McCann, Samuel M.

doi:10.1159/000110645

Cited by 10 publications

(6 citation statements)

References 45 publications

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“…However, TNF‐induced modulation of TTX‐insensitive Na + currents at the plasma membrane in DRG neurons following TNF receptor I activation seems to be secondary to an increase in p38 MAPK phosphorylation (37). In addition, TNFα can cause the release of proposed TRP agonists such as endocannabinoids that may be responsible for mediating some of the downstream actions of TNFα (40–42). In fact, it has been suggested that the TRPV1 antagonist SB‐366791 can act presynaptically on neurons terminating in the dorsal horn of the spinal cord to inhibit glutamatergic transmission, a response that is blocked by SB‐366791 after peripheral inflammation (43).…”

Section: Discussionmentioning

confidence: 99%

A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis

Fernandes¹,

Russell²,

Spina³

et al. 2011

Arthritis & Rheumatism

157

146

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Objective. To investigate the involvement of transient receptor potential ankyrin 1 (TRPA1) in inflammatory hyperalgesia mediated by tumor necrosis factor ␣ (TNF␣) and joint inflammation.Methods. Mechanical hyperalgesia was assessed in CD1 mice, mice lacking functional TRP vanilloid 1 (TRPV1 ؊/؊ ) or TRPA1 (TRPA1 ؊/؊ ), or respective wildtype (WT) mice. An automated von Frey system was used, following unilateral intraplantar injection of TNF␣ or intraarticular injection of Freund's complete adjuvant (CFA). Knee swelling and histologic changes were determined in mice treated with intraarticular injections of CFA.Results. TNF␣ induced cyclooxygenase-independent bilateral mechanical hyperalgesia in CD1 mice. The selective TRPV1 receptor antagonist SB-366791 had no effect on mechanical hyperalgesia when it was coinjected with TNF␣, but intrathecally administered SB-366791 attenuated bilateral hyperalgesia, indicating the central but not peripheral involvement of TRPV1 receptors. A decrease in pain sensitivity was also observed in TRPV1 ؊/؊ mice. Intraplantar coadministration of the TRPA1 receptor antagonist AP-18 with TNF␣ inhibited bilateral hyperalgesia. Intrathecal treatment with AP-18 also reduced TNF␣-induced hyperalgesia. CFA-induced mechanical hyperalgesia in CD1 mice was attenuated by AP-18 (administered by intraarticular injection 22 hours after the administration of CFA). Furthermore, intraarticular CFA-induced ipsilateral mechanical hyperalgesia was maintained for 3 weeks in TRPA1 WT mice. In contrast, TRPA1 ؊/؊ mice exhibited mechanical hyperalgesia for only 24 hours after receiving CFA.Conclusion. Evidence suggests that endogenous activation of peripheral TRPA1 receptors plays a critical role in the development of TNF␣-induced mechanical hyperalgesia and in sustaining the mechanical hyperalgesia observed after intraaarticular injection of CFA. These results suggest that blockade of TRPA1 receptors may be beneficial in reducing the chronic pain associated with arthritis.Sensory nerves consisting of C and A␦ nerve fibers innervate joints and skin and are often located in close association with blood vessels (1-3). Nerve stimulation in inflamed joints is considered to play a primary role in arthritis-related pain, and sensory afferent nerves have been located in joints, where they terminate in subsynovial connective tissue (4). Certain members of the transient receptor potential (TRP) receptor family, which are expressed on sensory nerves, are involved as key molecular integrators in the initiation and maintenance of joint pain, although the precise mechanisms involved are unclear (5,6).

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Section: Discussionmentioning

confidence: 99%

A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis

Fernandes¹,

Russell²,

Spina³

et al. 2011

Arthritis & Rheumatism

157

146

View full text Add to dashboard Cite

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“…8 The tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine, i.e., its increase indicates an inflammation in the body. 9 Interleukin-10 (IL-10)…”

Section: Introductionmentioning

confidence: 99%

Ethanol during adolescence decreased the BDNF levels in the hippocampus in adult male Wistar rats, but did not alter aggressive and anxiety-like behaviors

Scheidt

Fries

Stertz

et al. 2015

Trends Psychiatry Psychother.

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Objective:To investigate the effects of ethanol exposure in adolescent rats during adulthood by assesssing aggression and anxiety-like behaviors and measuring the levels of inflammatory markers.Methods:Groups of male Wistar rats (mean weight 81.4 g, n = 36) were housed in groups of four until postnatal day (PND) 60. From PNDs 30 to 46, rats received one of three treatments: 3 g/kg of ethanol (15% w/v, orally, n = 16), 1.5 g/kg of ethanol (12.5% w/v, PO, n = 12), or water (n = 12) every 48 hours. Animals were assessed for aggressive behavior (resident x intruder test) and anxiety-like behaviors (elevated plus maze) during adulthood.Results:Animals that received low doses of alcohol showed reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus as compared to the control group. No significant difference was found in prefrontal cortex.Conclusions:Intermittent exposure to alcohol during adolescence is associated with lower levels of BDNF in the hippocampus, probably due the episodic administration of alcohol, but alcohol use did not alter the level agression toward a male intruder or anxiety-like behaviors during the adult phase.

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“…1 h after treatment. Kopach et al 24 , Prestifillipo et al 17 , and Rettori et al 42 each offered pharmacological evidence for CB2 receptor regulation of salivation. We have previously shown that several nominally selective CB2 agonists/antagonists (JWH15/AM630) also work well at CB1 receptors 43 .…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid CB1 receptors regulate salivation

Andreis

Billingsley

Shirazi

et al. 2022

Sci Rep

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Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgren’s syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of salivation. We examined expression of cannabinoid CB1 receptors in submandibular salivary gland using immunohistochemistry and tested regulation of salivation by THC and cannabinoid-related ligands. We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the submandibular gland. No staining is seen in submandibular gland epithelial cells (acinar and ductal), or myoepithelial cells (MECs). Treatment with THC (4 mg/kg, IP) or the cannabinoid receptor agonist CP55940 (0.5 mg/kg) reduced salivation in both male and female mice 1 h after treatment. CBD had no effect on its own but reversed the effect of THC in a concentration-dependent manner. Neither the CB1 receptor antagonist SR141716 (4 mg/kg) nor the CB2-selective agonist JWH133 (4 mg/kg) had an effect on salivation. We also found that fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide and related lipids, regulates salivation. Salivation was reduced in FAAH knockout mice as well as mice treated with the FAAH blocker URB597 (4 mg/kg). URB597 had no effect in CB1 knockout mice. FAAH protein is detected intracellularly in acinar but not ductal epithelial cells. In lipidomics experiments, we found that FAAH knockout mice chiefly had elevated levels of acylethanolamines, including anandamide, and reduced levels of acyglycines. Our results are consistent with a model wherein endocannabinoids activate CB1 receptors on cholinergic axons innervating the submandibular gland. THC likely acts by plugging into this system, activating CB1 receptors to reduce salivation, thus offering a mechanism underlying the dry mouth reported by cannabis users.

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Endocannabinoids in TNF-α and Ethanol Actions

Cited by 10 publications

References 45 publications

A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis

A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis

Ethanol during adolescence decreased the BDNF levels in the hippocampus in adult male Wistar rats, but did not alter aggressive and anxiety-like behaviors

Cannabinoid CB1 receptors regulate salivation

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