Non-nociceptive roles of opioids in the CNS: opioids’ effects on neurogenesis, learning, memory and affect

Abstract

Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use. We provide new insights into how the dysregulation of neurogenesis by opioids can modify learning and affect, mood and emotions, processes that have been well accepted to motivate addictive behaviours.

Inspiratory rhythmogenic activity is burst-independent and opioid-sensitive

“…Morbidity and mortality from opioid addiction and overdose is largely a result of opioid-induced depression of breathing (Jaffe & Martin, 1990). Opiates given systemically will act on opioid receptors throughout the nervous system (Kibaly et al, 2019), and μORs are expressed in various brain structures regulating breathing (Gray et al, 1999; Manzke et al, 2003; Phillips et al, 2012; Pokorski and Lahiri, 1981; Prkic et al, 2012; Zhang et al, 2007; Zhang et al, 2011). While depression of breathing is unlikely to be dependent on actions at a single site (Lalley et al, 2014; Montandon and Horner, 2014; Stucke et al, 2015), our data is consistent with compelling in vitro and in vivo evidence that the preBötC is the most sensitive site to μOR agonists and that it mediates respiratory frequency depression by opioids (Ballanyi and Ruangkittisakul, 2009; Feldman and Del Negro, 2006; Feldman et al, 2013; Janczewski et al, 2002; Montandon and Horner, 2014; Montandon et al, 2011).…”

Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome

“…Next, we measured the mean grey value or average pixel density of the CD68+ cells. This analysis revealed that the DHA group had a significant decrease in mean density compared to the control diet group, regardless of opioid exposure (F (3,18) = 83.17, p<0.001 in each diet group) ( Figure 5D). However, there was no effect of opioid self-administration in either diet group (p=0.4 in each diet group) ( Figure 5D).…”

“…These included an over-prescription of potent and synthetic opioids, a belief that chronic pain was protective against the development of addictive behavior, an aggressive marketing strategy by the manufacturers, and the incorrect translation that long-term use of extended release opioids, safe in terminally-ill cancer patients, could be used in non-cancer patients without caution [1]. Alarming statistics from recent years document the increase in mortality from the use of fentanyl other synthetic opioids that are often prescribed for pain [2][3][4][5]. For many of these cases, the initial exposure to opioids began with oxycodone and other prescription analgesics and was then transferred to other more rapidly acting opioids [6].…”

Farmacología y Epidemiología de Opioides

“…todas estas acciones conllevan a una reducción de la excitabilidad neuronal, con la consecuente disminución del tráfico de información nociceptiva en la vía del dolor y el respectivo logro de analgesia. Luego de un tiempo, el GTP es convertido en GDP, con lo cual el sistema retorna a su estado inicial de inactivación, con la reasociación de las tres subunidades de la proteína G. 1) el control en la ingesta de alimentos y medicamentos esta regulado por MORs ubicados en la corteza prefrontal (CPF); 2) La activación de MOR en el cingulado anterior, el tálamo, tronco encefálico y médula espinal pueden inducir analgesia, respiración lenta y relajación; 3) La percepción sensorial puede verse influenciada por MOR en los lóbulos parietal y temporal; 4) La motivación, el deseo y el aprendizaje disociativo implican la estimulación de MOR en el núcleo accumbens (NAc), núcleo caudado, putamen caudado (PC), área tegmental ventral (ATV) y sustancia negra (SN); 5) la amígdala (AMIG) se requiere para el aprendizaje condicionado y la respuesta emocional; 6) La activación de MOR en el hipocampo (HIP) puede alterar el aprendizaje y neurogénesis; 7,8) MOR está presente tanto en el locus coeruleus como en el cerebelo, estructuras importantes en el estrés y la abstinencia de drogas (modificado de Kibaly et al, 2019).…”

“…1) Control of food and drug intake is regulated by MOP in the prefrontal cortex (PFC); 2) analgesia, slow breathing and relaxation can be induced by the activation of MOP in the anterior cingulate, thalamus, brainstem nuclei, and spinal cord 3) sensory perception can be influenced by MOP in parietal and temporal cortices; 4) motivation, desire and associative learning involve stimulation of MOP in the nucleus accumbens (NAc), caudate-putamen (CPu) nuclei, ventral tegmental area (VTA) and substantia nigra (SN); 5) MOP is expressed in the amygdala (AMG), which is required for emotional conditioned learning and responses; 6) MOP activation in the hppocampus (HIPP) can alter learning and neurogenesis; 7,8) and MOP is present in both the locus coeruleus, a structure important in stress and drug withdrawal, and the cerebellum. (Modified from Kibaly et al, 2019). (Soleimanpour et al, 2016).…”