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

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

Research output: Contribution to journalArticle

Abstract

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 CB1Rs 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 Δ9-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 Δ9-THC (6 mg/kg) in cisplatin-evoked neuropathic pain using wild-type mice. We also find that SP600125 causes an especially robust reduction in tolerance to the antinociceptive effects of Δ9-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 Δ9-THC, but not to CP55,940 or WIN55,212-2, demonstrating that the mechanisms of cannabinoid tolerance are agonist-specific.

Original languageEnglish (US)
Article number107847
JournalNeuropharmacology
Volume164
DOIs
StateAccepted/In press - Jan 1 2019

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Dronabinol
Cannabinoids
JNK Mitogen-Activated Protein Kinases
Cannabinoid Receptors
Neuralgia
Phosphotransferases
Mitogen-Activated Protein Kinase 9
G-Protein-Coupled Receptor Kinases
Cannabinoid Receptor Agonists
Arrestin
Acute Pain
Pain Measurement
Chronic Pain
Morphine
Opioid Analgesics
Cisplatin
Tail
Down-Regulation
Phosphorylation
3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Henderson-Redmond, A. N., Nealon, C. M., Davis, B. J., Yuill, M. B., Sepulveda, D. E., Blanton, H. L., ... Morgan, D. J. (Accepted/In press). c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner. Neuropharmacology, 164, [107847]. https://doi.org/10.1016/j.neuropharm.2019.107847
Henderson-Redmond, Angela N. ; Nealon, Caitlin M. ; Davis, Brian J. ; Yuill, Matthew B. ; Sepulveda, Diana E. ; Blanton, Henry L. ; Piscura, Mary K. ; Zee, Michael L. ; Haskins, Chris P. ; Marcus, David J. ; Mackie, Ken ; Guindon, Josée ; Morgan, Daniel J. / c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner. In: Neuropharmacology. 2020 ; Vol. 164.
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Henderson-Redmond, AN, Nealon, CM, Davis, BJ, Yuill, MB, Sepulveda, DE, Blanton, HL, Piscura, MK, Zee, ML, Haskins, CP, Marcus, DJ, Mackie, K, Guindon, J & Morgan, DJ 2020, 'c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner', Neuropharmacology, vol. 164, 107847. https://doi.org/10.1016/j.neuropharm.2019.107847

c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner. / Henderson-Redmond, Angela N.; Nealon, Caitlin M.; Davis, Brian J.; Yuill, Matthew B.; Sepulveda, Diana E.; Blanton, Henry L.; Piscura, Mary K.; Zee, Michael L.; Haskins, Chris P.; Marcus, David J.; Mackie, Ken; Guindon, Josée; Morgan, Daniel J.

In: Neuropharmacology, Vol. 164, 107847, 01.03.2020.

Research output: Contribution to journalArticle

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T1 - c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner

AU - Henderson-Redmond, Angela N.

AU - Nealon, Caitlin M.

AU - Davis, Brian J.

AU - Yuill, Matthew B.

AU - Sepulveda, Diana E.

AU - Blanton, Henry L.

AU - Piscura, Mary K.

AU - Zee, Michael L.

AU - Haskins, Chris P.

AU - Marcus, David J.

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AU - Guindon, Josée

AU - Morgan, Daniel J.

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Henderson-Redmond AN, Nealon CM, Davis BJ, Yuill MB, Sepulveda DE, Blanton HL et al. c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner. Neuropharmacology. 2020 Mar 1;164. 107847. https://doi.org/10.1016/j.neuropharm.2019.107847