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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Pre-treatment with WIN 55,212 resulted in a mean leftward shift of -5.5-fold.
“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
Pre-treatment with CP 55,940 resulted in a mean leftward shift of -6.73-fold.
“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
Antinociception from the combination of CP 55,940 and morphine appeared to be achieved without an increase in abuse liability.
“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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Functional blockage of the cannabinoid receptor type 1 evokes a kappa‐opiate‐dependent analgesia
Sáez-Cassanelli, J. L., Fontanella, G. H., Delgado-Garcia, J. M., & Carrión, Á. M. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05000.x · Cited by 22 · see citing works
“Cannabinoidinduced analgesia is mediated, at least partially, by the release of spinal dynorphins (Pugh et al. 1996; Mason et al. 1999b; Welch and Eads 1999), suggesting that these peptides play an important role in the analgesic effect induced by cannabinoids.”
BackgroundCannabis: Time for Scientific Evaluation of This Ancient Remedy?
Sharpe, P., & Smith, G. (2000) · Anesthesia & Analgesia · doi:10.1097/00000539-200002000-00001 · Cited by 21 · see citing works
“Thus coadministration of these two compounds may produce synergistic effects (40), reducing the total amount of each that needs to be administered and thus reducing the incidence of side effects caused by systemic absorption or rostral spread within the central nervous system.”
BackgroundInteraction of Cannabis Use and Aging: From Molecule to Mind
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“Moreover, these results were consistent with the previous study which indicated that CB1-R and MOP receptors co-localized in somatodendritic profiles of the spinal cord (Pugh et al. 1996).”
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Hayduk, S. A., Hughes, A. C., Winter, R. L., Milton, M., & Ward, S. J. (2024) · Biomedicines · doi:10.3390/biomedicines12061145 · Cited by 17 · see citing works
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“It has been suggested that ∆9-THC enhances the antinociception of morphine by triggering the release of endogenous dynorphin (Pugh et al., 1996).”
BackgroundDynorphin-independent spinal cannabinoid antinociception
Gardell, L. R., Ossipov, M. H., Vanderah, T. W., Lai, J., & Porreca, F. (2002) · Pain · doi:10.1016/s0304-3959(02)00173-2 · Cited by 17 · see citing works
“Unlike antinociception, other behavioral effects (i.e. hypothermia or catalepsy) of CB1 agonists were suggested to be independent of kappa opioid receptor activation (Pugh et al., 1996; Smith et al., 1994).”
InfluentialClinical implications for cannabinoid use in the rheumatic diseases: Potential for help or harm?
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Cannabinoids and opioids share cAMP pathway in rat splenocytes
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“In the last few years, pharmacological interactions between these systems have been described (Pugh et al., 1996; Rowen et al., 1998; Rubino et al., 1997; Navarro et al., 2001), essentially limited to the antinociception and addictive properties.”
BackgroundCannabis: Time for Scientific Evaluation of This Ancient Remedy?
Sharpe, P. T., & Smith, G. (2000) · Anesthesia & Analgesia · doi:10.1213/00000539-200002000-00001 · Cited by 16 · see citing works
Neuropeptide VF Enhances Cannabinoid Agonist WIN55,212-2-Induced Antinociception in Mice
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Antitussive effect of WIN 55212-2, a cannabinoid receptor agonist
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“k-opioid agonists led to subsequent studies demonstrating the involvement of the endogenous k-opioid dynorphin in the antinociceptive effects of THC (Smith et al., 1994; Pugh et al., 1996).”
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“…opioid receptor agonists. k opioid receptors are thought to mediate, in part, antinociceptive, but not other (e.g., cataplexy) effects of cannabinoid receptor agonists (Smith et al., 1994) through spinal mechanisms and the release of endogenous opioids such as dynorphin B (Pugh et al., 1996, 1997).”
BackgroundCarey, L. M., Maguire, D. R., & France, C. P. (2023) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2023.109787 · Cited by 9 · see citing works
Prescribing Cannabinoids for Multiple Sclerosis
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The Development of Cannabinoids as Therapeutic Agents in the United States
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- 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 › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Pharmacology › 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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