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Parkinson’s disease (PD) is the second-most common neurodegenerative disorder, neuropathologically characterized by the aggregation of misfolded α-synuclein (α-syn) protein, which appears to be central to the onset and progression of PD pathology. Evidence from pioneering studies has highly advocated the existence of impaired autophagy pathways in the brains of PD patients. Autophagy is an evolutionarily conserved, homeostatic mechanism for minimizing abnormal protein aggregates and facilitating organelle turnover. Any aberration in constitutive autophagy activity results in the aggregation of misfolded α-syn, which, in turn, may further inhibit their own degradationleading to a vicious cycle of neuronal death. Despite the plethora of available literature, there are still lacunas existing in our understanding of the exact cellular interplay between autophagy impairment and α-syn accumulation-mediated neurotoxicity. In this context, clearance of aggregated α-syn via up-regulation of the autophagy–lysosomal pathway could provide a pharmacologically viable approach to the treatment of PD. The present Review highlights the basics of autophagy and detrimental cross-talk between α-syn and chaperone-mediated autophagy, and α-syn and macroautophagy. It also depicts the interaction between α-syn and novel targets, LRRK2 and mTOR, followed by the role of autophagy in PD from a therapeutic perspective. More importantly, it further updates the reader’s understanding of various newer therapeutic avenues that may accomplish disease modification via promoting clearance of toxic α-syn through activation of autophagy.

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The opioid crisis is a major threat of the 21st century, with a remarkable juxtaposition of use and abuse. Opioids are the most potent and efficacious class of analgesics, but despite their proven therapeutic efficacy, they have recently been degraded to third-line therapy for the management of chronic pain in clinics. The reason behind this is the development of potential side effects and tolerance after repeated dosing. Opioid tolerance is the major limiting factor leading to the withdrawal of treatment, severe side effects due to dose escalation, and sometimes even death of the patients. Every day more than 90 people die due to opioids overdose in America, and a similar trend has been seen across the globe. Over the past two decades, researchers have been trying to dissect the neurobiological mechanism of opioid tolerance. Research on opioid tolerance shifted toward central nervous system-based adaptations because tolerance is much more than just a cellular phenomenon. Thus, neurobiological adaptations associated with opioid tolerance are important to understand in order to find newer pain therapeutics. These adaptations are associated with alterations in ascending and descending pain pathways, reward circuitry modulations, receptor desensitization and down-regulation, receptor internalization, heterodimerization, and altered epigenetic regulation. The present Review is focused on novel circuitries associated with opioid tolerance in different areas of the brain, such as periaqueductal gray, rostral ventromedial medulla, dorsal raphe nucleus, ventral tegmental area, and nucleus accumbens. Understanding the neurobiological modulations associated with chronic opioid exposure and tolerance will pave the way for the development of novel pharmacological tools for safer and better management of chronic pain in patients.