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The role of endogenous opioids in enhancing the antinociception produced by the combination of delta 9-tetrahydrocannabinol and morphine in the spinal cord.
Abstract
We have shown previously that intrathecal (i.t.) administration of the combination of delta 9-tetrahydrocannabinol (THC) and morphine results in a greater than additive antinociceptive effect. Similarly, pretreating mice with subthreshold doses of the kappa agonist, Dynorphin A (1-8), produced a parallel, leftward shift of the morphine dose-response curve, shifting the ED50 of morphine from 0.32 to 0.04 micrograms/mouse. A cocktail of enzyme inhibitors used to prevent the metabolism of Dynorphin A (1-8) into the delta receptor agonist, [Leu5]-enkephalin, attenuated the enhancement of morphine-induced antinociception by delta 9-THC. The enhanced antinociceptive effect observed after i.t. administration of the combination of delta 9-THC and morphine was also attenuated with antisera to Dynorphin A (1-8) (10 micrograms/ mouse) and Dynorphin A (1-13) (10 micrograms/mouse). Antisera to Dynorphin A (1-8) and Dynorphin A (1-17) blocked the antinociceptive effects of delta 9-THC (50 micrograms i.t.) without producing any significant alteration in the hypothermic and cataleptic effects or hypomotility produced by delta 9-THC. The antinociception produced by the combination of delta 9-THC and morphine was blocked by the kappa antagonist, nor-binaltorphimine (2 micrograms/ mouse), as well as the delta antagonist, naltrindole (5 micrograms/ mouse). Thus, the antinociception of morphine, which is mediated predominately by mu receptors, may be enhanced by delta 9-THC through the activation of kappa and delta receptors.
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In the citing paper
“Pre-treatment with WIN 55,212 resulted in mean leftward shift of -5.5-fold.”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Pugh 1996
In the citing paper
“Pre-treatment with CP 55,940 resulted in a mean leftward shift to of -6.73-fold.”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Pugh 1996
In the citing paper
“Antinociception from the combination appeared to be achieved without an increase in abuse liability”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Pugh 1996
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Items 101–124 of 124
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Wardill, H. R., Wooley, L. T., Bellas, O. M., Cao, K., Cross, C., van Dyk, M., Kichenadasse, G., Bowen, J. M., Zannettino, A. C. W., Shakib, S., et al. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02466-w · Cited by 6
“In animal studies, either morphine or codeine produces synergistic antinociception when combined with THC [103 – 106], and similar synergies have been documented in humans [107].”
BackgroundOkada‐Ogawa, A., Kurose, M., & Meng, I. D. (2010) · Brain Research · doi:10.1016/j.brainres.2010.08.073 · Cited by 6
“Consequently, pretreatment with antisera to dynorphin A blocks THC, but not CP55,940 induced antinociception and THC shows cross tolerance with dynorphin A but not with dynorphin B (Pugh et al., 1996; Pugh et al., 1997).”
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“Moderate expression of CB 1 R has been observed in the spinal dorsal horn [51–54], and most recently, CB 1 R-positive fibers have been identified in the spinal ventral horn [55].”
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Miller, M. L., Chadwick, B. J., Morris, C. V., Michaelides, M., & Hurd, Y. L. (2015) · Springer eBooks · doi:10.1007/978-1-4939-2294-9_15 · Cited by 3
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Sánchez, M., & Miquel (2003) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) · Cited by 3
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McLemon, E., & Chesworth, R. (2021) · Neuroanatomy and Behaviour · doi:10.35430/nab.2021.e14 · Cited by 1
da Silva, J. A. (2011) · doi:10.11606/d.17.2011.tde-14082013-123119
Roloff, A. M. (2009) · University of Minnesota Digital Conservancy (University of Minnesota)
Garcia, G. Ò. (2011) · TDX (Tesis Doctorals en Xarxa)
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“In terms of mechanism of action, it is demonstrated that cannabinoids release endogenous opioids which stimulate both delta and kappa opioid receptors (Welch & Eads, 1999; Smith et al., 1994; Pugh et al., 1996).”
In vivo analysis of the antihyperalgesic activity of innovative compounds
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Metadata
- Authors
- Pugh, G., Smith, P. B., Dombrowski, D. S., & Welch, S. P.
- Affiliations
- Virginia Commonwealth University (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1996-11
- Volume
- 279
- Issue
- 2
- Pages
- 608-616
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1907921830
- Cited by
- 123
- References
- 0
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 2 · 2012: 3
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institutes of Health (5k02da000186-09)
- National Institute on Drug Abuse (DA 05274, DA‐03672, KO2 DA00186)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Keywords
- endogenous opioids, delta-9-tetrahydrocannabinol, morphine, antinociception, spinal cord, dynorphin A, kappa opioid receptor, delta opioid receptor, mu-opioid receptor, nor-binaltorphimine, naltrindole, leu-enkephalin, intrathecal administration
- MeSH terms
- Analgesia, Analgesics, Animals, Body Temperature, Calcium, Catalepsy, Drug Synergism, Dynorphins, Male, Morphine, Rabbits, Spinal Cord, Dronabinol, Receptors, Opioid, delta, Receptors, Opioid, kappa, Mice
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