c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner

NEUROPHARMACOLOGY

卷:164

Article

Henderson-Redmond, Angela N.¹  Nealon, Caitlin M.¹  Davis, Brian J.^2,3  Yuill, Matthew B.¹  Sepulveda, Diana E.¹  Blanton, Henry L.⁴  Piscura, Mary K.¹  Zee, Michael L.^1,2,3  Haskins, Chris P.^1,2,3  Marcus, David J.^1,2,3  Mackie, Ken^2,3  Guindon, Josee⁴  Morgan, Daniel J.¹ 

[1] Penn State Univ, Coll Med, Dept Anesthesiol & Perioperat Med, Hershey, PA 17033 USA

[2] Indiana Univ, Gill Ctr Biomol Sci, Bloomington, IN 47405 USA

[3] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA

[4] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Lubbock, TX 79430 USA

关键词: Cannabinoid;    CB1R;    THC;    Pain;    JNK;    Tolerance;    Mouse;    Arrestin;    GPCR;   

DOI  :  10.1016/j.neuropharm.2019.107847

来源: Elsevier

【 摘 要 】

Tolerance to the antinociceptive effects of cannabinoids represents a significant limitation to their clinical use in managing chronic pain. Tolerance likely results from desensitization and down-regulation of the cannabinoid type 1 receptor (CB1R), with CB1R desensitization occurring via phosphorylation of CB(1)Rs by a G proteincoupled receptor kinase and subsequent association with an arrestin protein. Previous studies have shown that (1) desensitization-resistant S426A/S430A mice exhibit a modest delay in tolerance for Delta(9)-THC and (-)-CP55,940 but a more pronounced disruption in tolerance for WIN 55,212-2 and (2) that c-Jun N-terminal kinase (JNK) signaling may selectively mediate antinociceptive tolerance to morphine compared to other opioid analgesics. In the current study, we found that pretreatment with the JNK inhibitor SP600125 (3 mg/kg) attenuates tolerance to the antinociceptive in the formalin test and to the anti-allodynic effects of Delta(9)-THC (6 mg/kg) in cisplatinevoked neuropathic pain using wild-type mice. We also find that SP600125 causes an especially robust reduction in tolerance to the antinociceptive effects of Delta(9)-THC (30 mg/kg), but not WIN 55,212-2 (10 mg/kg) in the tailflick assay using S426A/S430A mice. Interestingly, SP600125 pretreatment accelerated tolerance to the antinociceptive and anti-allodynic effects of (-)-CP55,940 (0.3 mg/kg) in mice with acute and neuropathic pain. These results demonstrate that inhibition of JNK signaling pathways delay tolerance to Delta(9)-THC, but not to CP55,940 or WIN55,212-2, demonstrating that the mechanisms of cannabinoid tolerance are agonist-specific.

【 授权许可】

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