Morphine is the essential opioid drug that use in the clinic to attenuate chronic and severe pain. However long-term administration of morphine leads to the development of anti-nociceptive morphine tolerance. Mechanisms that involved in morphine tolerance are complicated and affect a different part of CNS and change neural circuits. One of the most critical candidates for the development of morphine tolerance are neurotransmitters Which makes the communication between neurons and establish neural circuits. The most prominent neurotransmitters that involved in the development of morphine tolerance are NMDA one of the most popular excitatory neurotransmitter, GABA most important inhibitory neurotransmitter in CNS, and monoaminergic neurotransmitters: dopamine, noradrenaline, adrenaline and serotonin have a lot of crucial roles in CNS. Also, Changes that occur in the level of opioid receptors, neurotransmitters and its receptors make alternation cross-talk between neurons. Understanding these changes help us to have an overall concept about the development of morphine tolerance.
Background: Tolerance and dependence to anti-nociceptive effect of morphine restricted its use. Nowadays coadministration of morphine and other drugs suggests diminishing this tolerance. Baclofen is one of the drugs that may be beneficial in the attenuation of tolerance to morphine. Studies have shown that changes in TRPV-1 expression during administration of morphine have a pivotal role in developing morphine tolerance. Therefore, the effect of baclofen on TRPV-1 expression during chronic administration of morphine was investigated in this study. Methods: A total of 48 rats were divided into four groups of control, morphine single injection, morphine tolerance, and morphine tolerance + baclofen. To induce morphine tolerance in rats, animals received 10 mg/kg of i.p. morphine sulfate once a day for 10 days. In the treatment group, baclofen (0.5 mg/kg) was injected for 10 days, before morphine injection. Finally, to evaluate baclofen treatment on morphine analgesia and hyperalgesia, thermal hyperalgesia and formalin test were used. TRPV-1 and PKC expression and protein production in DRG of spinal cord were then evaluated by real-time PCR and Western blot. Results: In baclofen treatment group, thermal hyperalgesia and formalin test improved in comparison with morphine tolerance group. In morphine tolerance group, both TRPV-1/PKC gene expression and protein levels increased in comparison with the control group. However, following the baclofen treatment, the TRPV-1 and PKC levels decreased. Conclusion: Baclofen can enhance anti-nociceptive effect of morphine by modulating TRPV-1 channel and PKC activity.
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