FUNCTIONAL INTERACTIONS BETWEEN OPIOIDS AND A CANNABINOID RECEPTOR 2 AGONIST IN INFLAMMATORY PAIN.

Open Access
- Author:
- Yuill, Matthew Buchanan
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- November 03, 2017
- Committee Members:
- Daniel James Morgan, Dissertation Advisor/Co-Advisor
Patricia Sue Grigson-Kennedy, Committee Chair/Co-Chair
Robert G Levenson, Committee Member
John Ellis, Committee Member
Jossee Guindon, Outside Member - Keywords:
- CB2R
morphine
pain
tolerance
formalin
JWH-133
opioid
cannabinoid agonist - Abstract:
- The goal of this study was to test the hypothesis that the Cannabinoid 2 Receptor (CB2R) functionally interacts with the opioid system to modulate inflammatory pain. Additionally, we tested mechanisms mediating tolerance to multiple opioids, and to the prototypical cannabinoid Δ9-THC. CB2R agonists produce low levels of side effects and no tolerance relative to other opioid and cannabinoid agonists, making them an attractive pharmacotherapeutic target. This study assessed the anti-nociceptive effects of a selective CB2R agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with the activity of opioids in this model. JWH-133 produces dose-dependent anti-nociception during both the acute pain and inflammatory pain phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. The efficacy of JWH-133 was blocked by application of a CB2R selective antagonist (SR144528). After eleven once-daily injections of 1 mg/kg JWH-133, no tolerance was observed in the formalin test. Conversely, wild-type mice become tolerant to Δ9-THC, morphine, and fentanyl within eleven days. Cross-tolerance for the anti-nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant CB2R and Mu opioid receptor (MOR) interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH-133 response in both phases of the formalin test compared to vehicle treated morphine-naïve animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine. Similar results were found for cross-tolerance between JWH-133 and fentanyl, suggesting opioid and CB2R cross-tolerance is unidirectional in this model. However, preliminary data suggests co-administration of JWH-133 with morphine modestly attenuates morphine tolerance in the formalin model. Furthermore, isobolographic analysis revealed that co-administration of a fixed-ratio combination of JWH-133 and morphine has an additive effect on anti-nociception in the formalin test. Overall these findings show that CB2R may functionally interact with MOR to modulate anti-nociception and tolerance in inflammatory pain, which suggests clinical utility.