Abstract 2411 Relationship between Opioid Receptors and Naloxone

Opioid receptors are a part of the seven transmembrane G-protein coupled receptors (GPCR) residing within the cell membrane. The G protein has three classical opioid receptors DOP, KOP, and MOP (mu, delta, and kappa) all with higher "sensitivity to the opioid antagonist naloxone" (McDonald, 2015). The focus is on MOP or the mu-opioid receptor which is found in the Central Nervous System (CNS) within areas that are associated with "sensory and motor function, including regions concerned with the integration and perception of senses" (McDonald, 2015). The function of opioid receptors is to control different aspects of cellular function and neurotransmitter processes (Dhaliwal et.al, 2023). They are found at the pre and postsynaptic sites of the ascending pain transmission system in the dorsal horn of the spinal cord, the brain stem, thalamus, and the cortex. Typically, natural opioid chemicals such as Enkephalin bind to MOP receptors on the surface of neurons and supply the body by creating cyclic adenosine monophosphate (cAMP) through ATP, which ultimately triggers the release of noradrenaline (NA) and helps the body maintain normal levels of alertness, muscle tone, respiration (Kosten and George, 2023). The MOP receptors have many functions such as "neuromodulat[ing] different physiological functions, primarily nociception but also stress, temperature, respiration, endocrine activity" (Herman, 2023). In recent years there has been a growing presence of fentanyl, a synthetic opioid, within illegally purchased narcotics leading to more overdoses, requiring more doses of naloxone to be available. Opioids such as fentanyl and morphine act at the MOP receptor, as it is directly associated with feelings of analgesia. Naloxone is an opioid antagonist, which prevents the effects of opioids by rapidly reversing the effects of an overdose. This drug is administered either through injection or a nasal spray and binds to MOP receptors to block the effects of opiates and restore normal respiration for people whose breathing has slowed or stopped due to an opioid overdose. Despite naloxone having a low oral bioavailability, it has a fast onset of action following parenteral administration, resulting in rapid reversal of acute adverse opioid effects (Opioid Pharmacology, 2008). However, naloxone is only a temporary treatment and its effects do not last long, so medical attention is necessary as soon as naloxone is administered (Trescot et.al, 2023). Naloxone interacts with the opioid receptors either directly or indirectly, but the main receptor focused in several clinical trials has been the MOP receptor, whose PDB code is 8EF6: Morphine-bound mu-opioid receptor-Gi complex. Therefore, when MOP receptors are activated through an opioid antagonist, like naloxone, it activates in the midbrain which leads to the formation of descending inhibitory impulses. These descending inhibitory impulses travel to the periaqueductal gray which plays a role in the behavioral responses to threatening stimuli (Dhaliwal and Gupta, 2023). This stimulates descending inhibitory neurons connecting with Enkephalin-containing neurons and decreases nociceptive transmission. The use of presynaptic MORs activation and postsynaptic binding to MORs ultimately allows for opioid receptors to decrease in the transmission of pain signals from the periphery to the thalamus, contributing to the analgesic effects of opioids (Herman et.al, 2023) which essentially allows MOP receptors and naloxone to work against overdose.