THC−methadone and THC−naltrexone interactions on discrimination, antinociception, and locomotion in rats
Abstract
This study examined cannabinoid-opioid interactions within the same subjects on measures of discrimination, antinociception, horizontal locomotion, and catalepsy. Male Sprague-Dawley rats were trained to discriminate Δ(9)-tetrahydrocannabinol (THC, 3 mg/kg) from vehicle. THC alone (0.32-10 mg/kg) dose-dependently increased THC-appropriate lever responding and decreased response rate. THC alone also produced paw pressure antinociception and decreased locomotor activity, but did not produce catalepsy. Methadone (0.32-5.6 mg/kg) and naltrexone (0.32-3.2 mg/kg) alone produced low THC-appropriate lever responding up to doses that decreased response rate. When combined with THC, methadone (1.0 mg/kg) flattened the THC discrimination curve, but did not affect antinociceptive or motoric effects of THC. Naltrexone did not alter any effects of THC. In rats that were not trained to discriminate THC from vehicle, 1.0 mg/kg methadone did enhance THC antinociception. These results suggest that μ-opioid receptor agonists can disrupt the discriminative stimulus effects of cannabinoids while not significantly altering their antinociceptive or motoric effects, in chronically drug-exposed subjects. Further research is required to determine whether opioid enhancement of cannabinoid antinociception is limited to acute exposure, or simply requires higher doses in chronically drug-exposed subjects.
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The rats trained for drug discrimination tasks had received repeated administration of opioids and cannabinoids over many months and may have been tolerant to drug effects at the doses administered.
“The rats trained for drug discrimination tasks had received repeated administration of opioids and cannabinoids over many months and may have been tolerant to drug effects at the doses administered”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Wakley 2011
In opioid and delta-9-THC naïve rats, methadone 1.0 mg/kg significantly enhanced the antinociceptive effect of delta-9-THC, but this was not observed in rats previously trained for drug discrimination tasks.
“In opioid and delta-9-THC naïve rats, methadone 1.0 mg/kg significantly enhanced the antinociceptive effect of delta-9-THC, however this was not observed in rats that were previously trained for drug discrimination tasks.”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Wakley 2011
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Foll, B. L. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110065 · Cited by 32 · see citing works
Naltrexone does not attenuate the effects of intravenous Δ9-tetrahydrocannabinol in healthy humans
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“…multiple doses in mixtures have generally used only one ratio of opioid to cannabinoid (Cichewicz et al., 2005; Tham et al., 2005; Cox et al., 2007; Wakley and Craft, 2011; Kazantzis https://doi.org/10.1016/j.ejphar.2017.11.038 Received 29 June 2017; Received in revised form 15 November 2017;…”
InfluentialAquino, J. P. D., Meyerovich, J., Xie, C. Z., Ranganathan, M., Compton, P. A., Pittman, B. P., Rogan, M., & Sofuoglu, M. (2023) · Addiction Biology · doi:10.1111/adb.13317 · Cited by 19 · see citing works
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Assay of therapeutic ultrasound induced‐antinociception in experimental trigeminal neuropathic pain
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“In general, there is evidence that THC decreases locomotive activity in rats (Harte & Dow-Edwards, 2010; Shi et al., 2005; Wakley & Craft, 2011), has a dose-dependent effect on anxiety (Harte-Hargrove & Dow-Edwards, 2012; Keeley et al., 2015), and lowers rats’ weight-gain (Bruijnzeel et al., 2019;…”
BackgroundPearl‐Dowler, L., Posa, L., López-Canul, M., Teggin, A., & Gobbi, G. (2023) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110805 · Cited by 7 · see citing works
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“Both antagonistic and agonistic interactions between opioids and cannabinoids have been reported in animal (Maguire & France, 2016; Wakley & Craft, 2011) as well as in human studies (Haney, 2007).”
BackgroundSlivicki, R. A., Wang, J. G., Nhat, V. T. T., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.04.569809 · Cited by 3 · see citing works
“Yet, these data are in contrast to other reports in rats which suggest females are more sensitive(Tseng and Craft, 2001; Wakley and Craft, 2011a; Craft et al., 2012; Wakley et al., 2014)(for review see:(Cooper and Craft, 2018)) and reflect a species difference.”
THC modifies the impact of heroin delivered by vapor inhalation in ratsPreprint
Gutierrez, A., Nguyen, J. D., Creehan, K. M., Paydar, M. J., Grant, Y., & Taffe, M. A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.26.441541 · Cited by 2 · see citing works
“…often in the same direction, i.e., anti-nociceptive (Li et al., 2008; Lichtman and Martin, 1990; Manning et al., 2001; Peckham and Traynor, 2006; Wakley and Craft, 2011) and rewarding (Blakesley et al., 1972; Justinova et al., 2003; Killian et al., 1978; Panlilio et al., 2010; Vendruscolo et…”
BackgroundPharmacotherapy for Cannabis Use Disorder: Preclinical and Clinical Models
Bedillion, M. F., Moore, C. F., Weerts, E. M., Arout, C. A., Harris, H. M., & Haney, M. (2025) · Current topics in behavioral neurosciences · doi:10.1007/7854_2025_598 · Cited by 1 · see citing works
Moore, C. F., Bedillion, M. F., Haney, M., & Weerts, E. M. (2025) · Current Addiction Reports · doi:10.1007/s40429-025-00705-z
“Drug discrimination studies have shown mixed results with naltrexone, with studies showing either it reduces discriminative effects of THC or produces no change [118, 119 ].”
Morgan, M. M., & Hickey, C. M. (2026) · European Journal of Pain · doi:10.1002/ejp.70279
“However, caution must be used in interpreting these results because many of these studies use large doses of THC ( ≥ 3 mg/kg) known to inhibit movement (Wakley and Craft 2011; Wiley and Burston 2014).”
- Authors
- Wakley, A. A., & Craft, R. M.
- Affiliations
- Washington State University (US)
- Corresponding author
- Wakley, Alexa A.
- ORCID
- Craft, Rebecca M.
- Venue
- Behavioural Pharmacology
- Published
- 2011-09
- Volume
- 22
- Issue
- 5 and 6
- Pages
- 489-497
- ISSN
- 0955-8810 (ISSN-L)
- OpenAlex
- W2068736399
- Cited by
- 20
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 1 · 2018: 1 · 2017: 3 · 2015: 1 · 2012: 3
- FWCI
- 0.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Behavioural Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Washington State University
- Peter F. McManus Charitable Trust
- National Institute on Drug Abuse
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- delta-9-tetrahydrocannabinol, methadone, naltrexone, opioid-cannabinoid interaction, drug discrimination, antinociception, locomotor activity, catalepsy, mu-opioid receptor agonists, chronic drug exposure
- MeSH terms
- Analgesics, Opioid, Animals, Discrimination Learning, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Interactions, Locomotion, Male, Methadone, Naltrexone, Narcotic Antagonists, Pain, Dronabinol, Rats, Sprague-Dawley, Receptors, Opioid, mu, Analgesics, Non-Narcotic, Rats
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