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Papers of the Week

Papers: 23 Nov 2019 - 29 Nov 2019

Animal Studies, Pharmacology/Drug Development

2020 Mar 01



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


Henderson-Redmond AN, Nealon CM, Davis BJ, Yuill MB, Sepulveda DE, Blanton H, Piscura MK, Zee ML, Haskins CP, Marcus DJ, Mackie K, Guindon J, Morgan DJ
Neuropharmacology. 2020 Mar 01; 164:107847.
PMID: 31758947.


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 (CBR), with CBR desensitization occurring via phosphorylation of CBRs by a G protein-coupled 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 Δ-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 and anti-allodynic effects of Δ-THC (6 mg/kg) in wild-type mice using the formalin test and in mice with cisplatin-evoked neuropathic pain, respectively. We also find that SP600125 causes an especially robust reduction in tolerance to the antinociceptive effects of Δ-THC (30 mg/kg) but not WIN 55,212-2 (10 mg/kg) in the tail-flick 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 Δ-THC, but not to CP55,940 or WIN55,212-2, demonstrating that the mechanisms of cannabinoid tolerance are agonist-specific.