The DOI matches its Crossref record; 92 of the 92 references it cites were found in a registry or an index.
Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats
Abstract
Exogenous cannabinoids are effective in attenuating neuropathic pain behaviors induced by peripheral nerve injury, but the mechanisms of their effectiveness remain unclear. Here we examined the expression of spinal cannabinoid-1-receptors (CB1Rs) following chronic constriction sciatic nerve injury (CCI) and its relation to the effects of a CBR agonist (Win 55,212-2) on neuropathic pain in rats. CCI induced a time-dependent upregulation of spinal CB1Rs primarily within the ipsilateral superficial spinal cord dorsal horn as revealed by both Western blot and immunohistochemistry. This CCI-induced CB1R upregulation was at least in part mediated through tyrosine kinase receptors (Trk), because intrathecal treatment with the Trk inhibitor K252a (1 microg) for postoperative days 1-6 significantly reduced the CB1R upregulation in CCI rats. At the intracellular level, the mitogen-activated protein kinase (ERK-MAPK) inhibitor PD98059 (1 microg) prevented, while the protein kinase C inhibitor chelerythrine (10 microg) partially reduced, the CCI-induced CB1R upregulation when each agent was administered intrathecally for postoperative days 1-6. Importantly, the CCI-induced upregulation of spinal CB1Rs enhanced the effects of Win 55,212-2 on both thermal hyperalgesia and mechanical allodynia, since inhibition of the CB1R upregulation by PD98059 resulted in a significant reduction of the effects of Win 55,212-2 in CCI rats. These results indicate that upregulation of spinal CB1Rs following peripheral nerve injury may contribute to the therapeutic effects of exogenous cannabinoids on neuropathic pain.
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“CB1 receptors are upregulated in the spinal cord following CCI; these effects are believed to be modulated by tyrosine kinase38 and glucocorticoid39 receptors.”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [38]
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BackgroundNeuropathic pain: aetiology, symptoms, mechanisms, and management
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Pertwee, R. G. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707442 · Cited by 2,047
Zhuang, Z., Gerner, P., Woolf, C. J., & Ji, R. (2005) · Pain · doi:10.1016/j.pain.2004.12.022 · Cited by 774
Self-citationThe Endocannabinoid System and Pain
Guindon, J., & Hohmann, A. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709789824660 · Cited by 476
Emerging strategies for exploiting cannabinoid receptor agonists as medicines
Pertwee, R. G. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2008.00048.x · Cited by 436
Cannabinoids and Pain: New Insights From Old Molecules
Vučković, S., Srebro, D., Vujović, K. S., Vučetić, Č., & Prostran, M. S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01259 · Cited by 440
Metadata
- Authors
- Lim, G., Sung, B., Ji, R.-R., & Mao, J.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Mao, Jianren
- Venue
- Pain
- Published
- 2003-09
- Volume
- 105
- Issue
- 1
- Pages
- 275-283
- ISSN
- 0304-3959 (ISSN-L)
- OpenAlex
- W2007715028
- Cited by
- 195
- References
- 91
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 4 · 2018: 7 · 2017: 11 · 2016: 7 · 2015: 10 · 2014: 5 · 2013: 8 · 2012: 8
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Massachusetts General Hospital
- National Institutes of Health
- National Institute on Drug Abuse (DA 08835, R01DA008835)
- National Institute of Neurological Disorders and Stroke (R01NS040698, R01NS042661, R01 NS42661)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- cannabinoid 1 receptor, dorsal horn, neuropathic pain, chronic constriction injury, sciatic nerve injury, WIN 55,212-2, exogenous cannabinoids, receptor up-regulation, Trk receptors, K252a, ERK signaling, protein kinase C, thermal hyperalgesia, mechanical allodynia, intrathecal administration
- MeSH terms
- Analgesics, Animals, Behavior, Animal, Enzyme Inhibitors, Flavonoids, Ligation, Male, Morpholines, Naphthalenes, Neuralgia, Pain, Protein Kinase C, Receptors, Drug, Sciatic Nerve, Spinal Cord, Time Factors, Wounds and Injuries, Up-Regulation, Rats, Sprague-Dawley, Receptor Protein-Tyrosine Kinases, Mitogen-Activated Protein Kinases, Receptors, Cannabinoid, Benzoxazines, Rats
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