Carveol mitigates the development of the morphine anti-nociceptive tolerance, physical dependence, and conditioned place preference in mice.

Emergence of analgesic tolerance and dependence to morphine is frequently the limiting factor in the use of this agent in the management of pain. Hence, this study aimed to investigate the beneficial effects of the natural compound carveol (CV) against morphine antinociceptive tolerance, dependence and conditioned place preference (CPP) in mice. Behavioural paradigms included hot plate and tail-flick (for tolerance), observation of withdrawal signs (for dependence) while biochemical tests involved the assays for mRNA expression, nitrite levels, antioxidants, and immunohistochemistry studies. Behavioural tests indicated that treatment with CV significantly attenuated the morphine analgesic tolerance, physical dependence and CPP in mice. It was observed during biochemical analysis that CV-treated animals exhibited reduced mRNA expression of inducible nitric oxide synthase (iNOS) and NR2B (an NMDA subtype). In addition, decreased levels of nitrite were observed in mouse hippocampus following CV treatment than morphine administration only. Further, CV enhanced the neuronal innate antioxidants including Glutathione-S-Transferase (GST), glutathione (GSH) and catalase (CAT), while curtailed lipid peroxidase (LPO) levels in mice brain tissues. Moreover, CV exerted significant anti-inflammatory effects as evidenced by reduced expression of TNF-α and p-NF-κB in these animals than with morphine treatment only. Together, anti-inflammatory and antioxidant effects might confer needed neuro-protection following morphine administration. These observations warrant further investigations of the beneficial role of CV as a novel agent in overcoming the development of tolerance and physical dependence following morphine use.

Molecular mechanisms of morphine tolerance and dependence; novel insights and future perspectives.

Drug addiction is a devastating condition that poses a serious burden on the society. The use of some drugs like morphine for their tremendous analgesic properties is also accompanied with developing tolerance, dependence and the withdrawal symptoms. These symptoms are frequently severe enough to reinforce the person in recovery to start over the use of drug again and hinder the clinical use of drugs like morphine for chronic pain. Research into opioid receptors and related molecular pathways has seen resurgence in the wake of the growing opioid epidemic. The current study provides a comprehensive scientific exploration of the molecular mechanisms and underlying signalling in morphine tolerance and dependence. It also critically evaluates current therapeutic approaches, shedding light on their efficacy and limitations, and future prospects. The graphical abstract depicts an overview of the pathways involved in the emergence of morphine-related tolerance and dependence including NMDA, Nitric oxide, and PPAR, as well as behavioural sensitization along with present and future innovative treatment strategies including stem cell therapy that have been discussed in the current manuscript.

Emodin alleviates chronic constriction injury-induced neuropathic pain and inflammation via modulating PPAR-gamma pathway.

Neuropathic pain has been characterized as chronic pain resulting from pathological damage to the sensorimotor system. Because of its complex nature, it remains refractory to most of the therapeutic interventions, and surgical intervention and physiotherapy alongside steroidal treatments remain the only treatment protocols with limited success, hence solidifying the need to find efficacious therapeutic alternatives. Emodin was used as a post-treatment for its potential to be neuroprotective in the treatment of chronic constriction injury-induced NP. The first day following surgery, Emodin treatment began, and it lasted until the 21st day. On days 3, 7, 14 and 21, all behavioral investigations were conducted. The sciatic nerve and spinal cord were extracted for further molecular examination. Emodin elevated response latency, was able to delay the onset of mechanical hyperalgesia in rats on days 7, 14, and 21 and reduced the CCI-induced paw deformation. Emodin treatment significantly reduced lipid peroxidation and NO levels while restoring the GST, GSH and catalase. It significantly improved the disorientation of the sciatic nerve and spinal cord confirmed by H & E staining and reduced inflammatory markers as observed by the quantification of COX-2, TNF-α, p-NFκb and up-regulated PPAR-γ levels by ELISA and PCR. According to the findings, Emodin has antinociceptive and anti-hyperalgesic properties, which reduced pain perception and inflammation. We also suggested the involvement of PPAR-γ pathway in the therapeutic potential of emodin in chronic nerve injury.