Involvement of nitric oxide signaling mechanisms underlying opioid tolerance

Abstract

This work focuses on the study of neuropharmacological mechanisms underlying opioid tolerance, in particular, the involvement of NO signalling pathways. Opioids are potent drugs used for pain relief. However, their therapeutic potential is limited as their long-term use leads to the development of tolerance to their analgesic effects. Opioid tolerance is a complex phenomenon and the underlying mechanisms have not been fully elucidated. Understanding the ways in which tolerance can be attenuated would be a significant advantage in the therapeutic use of these agents. The noradrenergic nucleus locus coeruleus (LC) contains a high-density of MORs and it has been extensively used as a model to explore the cellular and molecular mechanisms underlying opioid tolerance. In this regard, there is substantial evidence showing the involvement of mu-opioid receptor (MOR) desensitization in the development of tolerance.The signaling messenger nitric oxide (NO) has been widely recognized to play pivotal roles in the regulation of multiple physiologic and pathophysiological processes. It is produced from L-arginine by the enzymatic action of NO synthase (NOS). The main target of NO is the enzyme soluble guanylyl cyclase (sGC), which catalyzes the formation of 3'5'-cyclic guanosine monophosphate (cGMP). This second messenger activates a number of effectors, such as the cGMP-dependent protein kinase (PKG). NO also reacts with oxygen derivatives to produce reactive oxygen and nitrogen species (ROS), such as the powerful oxidant molecule peroxynitrite. NO modulates opioid actions, as it was found to be involved in Met5-enkephalin (ME)-induced MOR desensitization in vitro and in the neuronal adaptations occurring in vivo during morphine tolerance. We carried out four studies to explore the role of NO and its downstream signaling pathways (sGC/cGMP and ROS) in the adaptations triggered by different opioid agonists both in vitro and in vivo.