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  • Accumulating evidence suggests that the NGF family

    2022-05-12

    Accumulating evidence suggests that the NGF family of neurotrophins have important modulatory roles in opioid analgesia and addiction [36]. The NGF family of neurotrophins include NGF, Bay 11-7085 derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4) [37]. BDNF knockout mice demonstrated reduction in the intensity of morphine withdrawal symptoms [38]. Intrathecal administration of NGF restored the effectiveness of morphine in attenuating hyperalgesia following peripheral nerve injury [39]. Additionally, a marked attenuation of morphine tolerance was observed in NT4 deficient transgenic mice, indicating that neurotrophin activity is involved in opioid tolerance and dependence [40]. In the present study we found that there was a significant decrease in NGF expression in the brain of mice that had undergone morphine or oxycodone tolerance. A similar decrease in NGF expression was also observed in mice that had undergone morphine or oxycodone tolerance with IRL-1620 treatment. Our results showing that repeated subcutaneous morphine or oxycodone injections decrease NGF and possibly neurogenesis, confirm the findings of a previous report that first observed a decrease in the expression of NGF in both morphine pellet implanted and heroin self-administering rats [5]. Since we found that expression of NGF is significantly decreased in opioid tolerance, and previously we have demonstrated that IRL-1620 increases VEGF and NGF expression in the infarcted hemisphere of the rat with cerebral ischemia [19], we wanted to examine the signaling pathway that involves both ETB receptors and NGF. One signaling pathway that is common to both ETB receptors and NGF is phosphoinositide 3-kinase (PI3K) pathway [41, 42]. Hence, we examined the expression of PI3K in the brains of mice following morphine or oxycodone tolerance. IRL-1620 did not produce any change in the expression of PI3K following morphine or oxycodone tolerance. However, we found that in mice that had undergone morphine or oxycodone tolerance, there was a significant decrease in the expression of PI3K in the brain. A similar decrease in the expression of PI3K was also observed in mice that had undergone morphine or oxycodone tolerance with IRL-1620 treatment. Overall, the data for the expression of PI3K is very similar to the data for the expression of NGF. Alteration in PI3K are a mirror image of NGF expression changes, suggesting that PI3K is involved in the signaling pathway of NGF. In contrast to our expectation, although IRL-1620 attenuated analgesic tolerance to morphine and oxycodone, but did not produce any change in the expression of NGF. IRL-1620 has been found to enhance [19, 20, 43] the neurorestorative processes that are endogenously induced in brain tissue in response to injury to the brain [44, 45]. Chronic exposure to drugs of abuse produces adaptive changes in various neurotrophic factors in the ventral tegmental neurons and other neurons of the brain [38, 46]. In the present study, there is evidence of adaptive change in the brain of mice that underwent morphine or oxycodone tolerance as indicated by a decrease in NGF expression following morphine or oxycodone tolerance. However, it is possible that adaptive change due to morphine or oxycodone tolerance did not initiate ETB receptor-mediated neuroprotective processes. The adaptive changes due to morphine or oxycodone tolerance are considered to be a reversible process [47] and may be different from those due to neurodegenerative diseases or traumatic brain injuries. This may explain why IRL-1620 did not produce angiogenesis and neurogenesis in morphine or oxycodone tolerance as observed in animal models of cerebral ischemia and Alzheimer’s disease [12, 19, 20, 43]. The notch signaling pathway is a highly conserved pathway that regulates neurogenesis [48, 49]. It is critical in the maintenance, proliferation, differentiation and apoptosis of neuronal stem cells [50, 51]. Notch expression in the sub-ventricular zone of the brain is decreased with aging and co-relates with reduced neurogenesis [52]. Blockage of notch signaling either by siRNA against notch reduced ischemia-mediated cell proliferation, and down-regulation of notch expression leads to an increase in neuronal proliferation [53]. Furthermore, it has been recently shown that autophagy degrades notch1 in primary neurons and induces neuronal stem cell proliferation and differentiation [54]. Neuronal damage results in disruption of the notch signaling pathway, which subsequently leads to neurogenesis [48, 49]. In summary these studies indicate that down-regulation of notch1 leads to increased neurogenesis and up-regulation of notch1 produces decreased neurogenesis indicating the importance of exploring notch signaling in opioid induced alteration in neurogenesis.