Morphine is widely used as an
analgesic to treat moderate to severe
pain, but chronic
morphine use is associated with development of tolerance and dependence, which limits its
analgesic efficacy. Our previous research has showed that nonanalgetic dose of a
cannabinoid type 2 (
CB2) receptor agonist reduced
morphine tolerance in
cancer pain. A previous study showed the colocalization of CB2 and transient receptor potential vanilloid 1 (TRPV1) in human and rat dorsal root ganglia (DRG) sensory neurons. Whether coadministration of a
CB2 receptor agonist and
morphine could reduce TRPV1 expression in morphine‑induced antinociception and tolerance in
cancer pain is unclear. Therefore, we investigated the effects of coadministration of a
CB2 receptor agonist
AM1241 and
morphine on TRPV1 expression and tolerance in
cancer pain. Coadministration of
AM1241 and
morphine for 8 days significantly reduced
morphine tolerance, as assessed by measuring paw withdrawal latency to a radiant heat stimulation, in Walker 256 tumor‑bearing rats. Repeated
morphine treatment for a period of 8 days induced upregulation of the TRPV1
protein expression levels in the DRG in the tumor‑bearing rats, although no change in
mRNA expression. Pretreatment with
AM1241 reduced this morphine‑induced upregulation of TRPV1 and the effect was reversed by the
CB2 receptor antagonist
AM630. Our findings suggest that coadministration of a
CB2 receptor agonist
AM1241 and
morphine reduced
morphine tolerance possibly through regulation of TRPV1
protein expression in the DRG in
cancer pain.