Activation of TRPV1 contributes to morphine tolerance: Involvement of the mitogen-activated protein kinase signaling pathway

Tolerance to the analgesic effects of opioids occurs after their chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we investigated the role of TRPV1, which is crucial for the transduction of noxious chemical and thermal stimuli, in morphine tolerance and tolerance-associated thermal hyperalgesia. After chronic morphine treatment, a marked increase in TRPV1 immunoreactivity (IR) was detected in L4 dorsal root ganglion (DRG) neurons, spinal cord dorsal horn, and sciatic nerve. Real-time reverse transcription (RT)-PCR demonstrated that TRPV1 mRNA was upregulated in spinal cord and sciatic nerve but not in the DRG. Intrathecal pretreatment with SB366791 [ N-(3-methoxyphenyl)- 4-chlorocinnamide], a selective antagonist of TRPV1, attenuated both morphine tolerance and associated thermal hyperalgesia. Chronic morphine exposure induced increases in phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPK-IR, extracellular signal-regulated protein kinase (ERK)-IR, and c-Jun N-terminal kinase (JNK)-IR, in L4 DRG neurons. Intrathecal administration of the selective p38, ERK, or JNK inhibitors not only reduced morphine tolerance and associated thermal hyperalgesia but also suppressed the morphine-induced increase of TRPV1-IR in DRG neurons, spinal cord, and sciatic nerve and of mRNA levels in spinal cord and sciatic nerve. Together, we have identified a novel mechanism by which sustained morphine treatment results in tolerance and tolerance-associated thermal hyperalgesia, by regulating TRPV1 expression, in a MAPK-dependent manner. Thus, blocking TRPV1 might be a way to reduce morphine tolerance.