Repeated Tetrahydrocannabinol Injections Induce Tolerance but Do Not Disrupt Ongoing Behaviour Upon Withdrawal in Male and Female Rats With Inflammatory Pain.
Michael M Morgan, Christa M. Hickey
European Journal of Pain May 1, 2026 DOI: 10.1002/ejp.70279 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study with experimental manipulation Peer reviewed |
|---|---|
| Population | Male and female Sprague-Dawley rats |
| Interventions | THC Complete Freund's Adjuvant (CFA) |
| Dose | 3 mg/kg/injection |
| Duration | 7-day injection period plus 6-day withdrawal assessment |
| Topics | Addiction Cannabis |
| Keywords | Sex differences Wheel running |
| Key findings | Persistent inflammatory pain does not alter the effects of repeated THC injections in male or female rats. |
Abstract
Many people use cannabis to self-medicate for pain. Little is known about the impact of pain on tolerance and spontaneous withdrawal to delta-9-tetrahydrocannabinal (THC), the primary psychoactive compound in cannabis. Our previous research with the opioid morphine suggests persistent pain will increase the magnitude and duration of THC withdrawal. Male and female Sprague-Dawley rats were individually housed in a cage with a running wheel to provide a continuous and objective measure of well-being. All rats were injected with Complete Freund's Adjuvant (CFA) into the right hindpaw to induce inflammatory pain. Beginning 1 day later, rats received twice daily THC or vehicle injections for 7 days followed by assessment of tolerance and spontaneous withdrawal. Administration of CFA decreased wheel running. Twice daily injections of THC (3 mg/kg/injection) caused a further reduction in running in male and female rats. Tolerance to the THC-induced decrease in running was more pronounced in male compared to female rats. There was no evidence of spontaneous withdrawal to THC despite continuous assessment for 6 days. Likewise, withdrawal had no effect on body weight. The lack of spontaneous withdrawal in rats with hindpaw inflammation is consistent with our recent study showing a lack of spontaneous withdrawal to THC in pain free rats, but opposite to our opioid research showing enhancement of spontaneous withdrawal to morphine in rats with hindpaw inflammation. In sum, persistent inflammatory pain does not appear to alter the effects of repeated THC injections in male or female rats. The use of THC as a treatment for pain is limited by side effects and tolerance but not by dependence associated withdrawal symptoms.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Repeated THC injections produced tolerance but no evidence of spontaneous withdrawal in rats with inflammatory pain.
Synthesized
Comparable studies
Other preclinical and animal studies on cannabis for addiction, most cited first.
Citations in the library
Cites 5
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- Tolerance but No Spontaneous Withdrawal Following Repeated THC Injections in Male and Female Rats Cannabis and Cannabinoid Research December 1, 2025
- Changes in striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence in male and female mice. Neuropsychopharmacology July 2022
- Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice. Drug and Alcohol Dependence October 1, 2018
- THC-methadone and THC-naltrexone interactions on discrimination, antinociception, and locomotion in rats. Behavioural Pharmacology September 2011