Activation of spinal PDGFRβ in microglia promotes neuronal autophagy via p38 MAPK pathway in morphine‐tolerant rats

Abstract

Morphine is the most potent analgesic in clinical treatment for various painful conditions. Long-term usage of morphine inevitably leads to the development of antinociceptive tolerance, which limits its clinical utilization (Christie, 2008;Wickham, 2017). For several decades, numerous studies have been devoted to illuminating the mechanisms underlying morphine tolerance, including nitric oxide-cyclic 3'-5' guanosine monophosphate signaling pathway, α 2 noradrenergic system cannabinoid system, and hyperexcitability of the central nervous system (Fisher et al., 2019;Gursoy et al., 2011;Ozdemir, 2020;Ozdemir et al., 2011). However, the neurobiological mechanisms of morphine tolerance are multifaceted and only partially understood.Macroautophagy, hereafter autophagy, is a lysosomal-dependent degradation pathway in eukaryotic cells, which is important for the generation of degradation products and intracellular clearance of defective macromolecules and organelles (Mizushima, 2018). Over the

Autophagy may protect the brain against prolonged consequences of headache attacks: A narrative/hypothesis review

“…These results provide some details of the mechanistic basis of the neuroinflammatory process that may be important in migraine pathogenesis and evidence that this process can be mediated by microglia autophagy 58 . The importance of P38 MAPK‐mediated autophagy in microglia was confirmed in morphine‐tolerant rats 59 . Upregulation of P2X4R and BDNF as well as an increase in phosphorylated extracellular regulated protein kinases and CGRP release in the TNC in a chronic migraine NTG‐induced animal model 47 .…”

“…58 The importance of P38 MAPK-mediated autophagy in microglia was confirmed in morphine-tolerant rats. 59 Upregulation of P2X4R and BDNF as well as an increase in phosphorylated extracellular regulated protein kinases and CGRP release in the TNC in a chronic migraine NTG-induced animal model. 47 Repeated administration of IVM, a P2X4R agonist, increased the levels of phosphorylated protein kinases, including p38 MAPK and CGRP release in the TNC.…”

Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in‐vitro analysis of cabergoline and Mdivi‐1 co‐treatment effects on the autophagy–apoptosis axis

“…Our research contributes to this area by suggesting that MTD treatment may exacerbate oxidative imbalance while also potentially enhancing antioxidant defense mechanisms. Additionally, we observed that morphine modulates synapses via ROS, instigating the activation of pathways related to endoplasmic reticulum stress, autophagy, and apoptosis 76–78 …”

The effect of cannabinoid type 2 receptor agonist on morphine tolerance

“…In the morphine tolerance model, TRPV1 increased, and when phosphorylated MAPK was inhibited, TRPV1 decreased correspondingly, suggesting that MAPK played a certein regulatory role in morphine induced by TRPV1 ( Chen et al, 2008 ). Studies have also shown that chronic morphine administration can activate platelet-derived growth factor receptor-β (PDGFRβ) signaling, which is a specific mediator that regulates opioid tolerance (Li [a] et al, 2020; Jia et al, 2021 ). Morphine treatment activates PDGFRβ, and PDGFRβ induces the activation and expression of HSP27 via the p38/MAPK and PI3K/Akt signaling pathways.…”

“…PGDFRβ-mediated HSP27 activation participates in morphine tolerance ( Li et al, 2020 ). In a model of morphine tolerance in rats, activating PDGFR in spinal microglia induced autophagy in GABAergic neurons via the p38/MAPK pathway, and autophagy inhibition attenuated the development of morphine tolerance ( Jia et al, 2021 ). The detailed mechanisms of PDGFR and autophagy deserve further exploration.…”