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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
Citations
Cited by
Sorted by citations
The effects of cannabinoids on the brain
Ameri, A. (1999) · Progress in Neurobiology · doi:10.1016/s0301-0082(98)00087-2 · Cited by 825
Cannabinoid receptors and pain
Pertwee, R. G. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00031-9 · Cited by 741
Pharmacological and biochemical interactions between opioids and cannabinoids
Manzanares, J., Corchero, J., Romero, J., Fernández‐Ruíz, J., Ramos, J. A., & Fuentes, J. (1999) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(99)01339-5 · Cited by 391
One Is Not Enough: Understanding and Modeling Polysubstance Use
Crummy, E. A., O’Neal, T. J., Baskin, B. M., & Ferguson, S. M. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00569 · Cited by 351
“Nicotine and opioid cross-tolerance is mediated by µO and nACh receptors (Haghparast et al., 2008; De Moura et al., 2019) while cannabinoid and opioid cross-tolerance is mediated by µO receptors and cannabinoid 1 (CB1) receptors (Pugh et al., 1994, 1996).”
BackgroundCannabinoid–Opioid Interaction in Chronic Pain
Abrams, D. I., Couey, P., Shade, S. B., Kelly, M. E., & Benowitz, N. L. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.188 · Cited by 319
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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