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Opioids' Effects on Neurogenesis, Learning, Memory

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Opioids' Effects on Neurogenesis, Learning, Memory REVIEWS Non- nociceptive roles of opioids in the CNS: opioids’ effects on neurogenesis, learning, memory and affect Cherkaouia Kibaly 1*, Chi Xu2, Catherine M. Cahill1, Christopher J. Evans1 and Ping- Yee Law1 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. opioid 1–3 Opioid The endogenous system consists of approximately in all hippocampal regions , including the dentate 5 A broad term used to 30 different opioid peptides, including β-endorphins, Met - gyrus (DG). The action of exogenous opioid drugs designate all substances, enkephalin and Leu5-enkephalin, orphanin FQ (also known in the hippocampus is likely involved in the effects of natural (for example, morphine) as nociceptin) and dynorphins. These opioid peptides bind opioids on learning and memory. Indeed, opioid drugs and synthetic (for example, fentanyl), that bind to opioid to their cognate G protein- coupled receptors, namely, the can impair anterograde and retrograde recall in patients 4 receptors in the nervous μ- opioid peptide receptor (MOP; also known as MOR), with pain . The other effect of opioids that is clearly system. δ- opioid peptide receptor (DOP; also known as DOR), linked to learning and memory is the development of κ- opioid peptide receptor (KOP; also known as KOR) and addiction. Addiction and relapse have been interpreted Hippocampus nociceptin opioid peptide receptor (NOP; also known as resulting from an abnormally robust memory formed A major anatomical structure 5 located in the medial temporal as OPRL1). The endogenous opioids and their receptors during the opioid- taking experience . Because the lobe of the mammalian brain are expressed by various cell types and widely distributed hippocampus is also included in the reward circuitry that processes a unidirectional throughout the body, including the central and peripheral (Fig. 2), the opioid- dependent mnesic effects are also flow of information via a nervous systems, immune cells, the adrenal medulla and associated with the extensively studied positive (that is, trisynaptic loop. the gonads, with the potential to modulate many different pleasure) and negative (that is, stress, depression and physiological and psychological processes (FIG. 1). From anxiety related to withdrawal) affect and emotion, as well the distribution of the opioid peptides throughout various as the incentive salience characterizing the consump- opiates6 1Department of Psychiatry brain regions, it is clear that the endogenous opioid system tion of . The role of opioids in regulating both and Biobehavioral Sciences, has functions beyond the modulation of pain perception. memory and affect, as well as emotion, is important in Semel Institute for For example, in addition to their actions at the spinal cord view of the current epidemiological context of opioid Neuroscience and Human and periaqueductal grey matter in modulating pain trans- drug addiction, which is at an all- time high in North Behavior, Shirley and Stefan mission, enkephalins are located within the amygdala, America, where opioid overdose is one of the leading Hatos Center for Neuropharmacology, where they regulate emotional responses. Their presence causes of death. Indeed, the concept that both affec- University of California, in the autonomic nuclei of the hypothalamus is important tive dysregulation and learning are the driving forces Los Angeles, CA, USA. for the regulation of cardiovascular and/or respiratory func- behind addictive behaviours, where the disruption of 2State Key Laboratory of tion, and they exert broad effects on anterior (and poste- consolidating the contextual memory associated with Natural Medicines, School rior) pituitary hormone secretion, including stimulating drug experiences and rewards may have therapeutic of Basic Medicine and Clinical the release of prolactin, growth hormone and adrenocorti- potential to prevent relapse6–8, has gained attention in Pharmacy, China 5 Pharmaceutical University, cotropic hormone and inhibiting the release of luteinizing the past decade . Nanjing, China. hormone, oxytocin and arginine vasopressin. The presence of opioid sites of action in the hippo- *e- mail: [email protected] The hippocampus is a key brain structure crucial in campus also explains the opioid modulation of neuro- https://doi.org/10.1038/ learning and memory, especially in contextual memory. genesis, which is a phenomenon that occurs in two s41583-018-0092-2 The opioid peptides and their receptors are expressed neurogenic brain regions, one of them being the DG9–16. NATURE REVIEWS | NEUROSCIENCE REVIEWS a Brain microglia Brain neurons Neuroinflammation • Feeding • Emotions • Pain • Motivation • Respiratory depression • Learning Spinal cord and dorsal • Sensory perception • Neurogenesis root ganglion • Stress Pain and sensory perception • Pleasure Lung Heart • Decrease respiration • Cardioprotection • Cancer • Heart rate Pancreas Weight gain Adrenal gland • Reduce cortisol • Affect immune and Kidney stress responses • Renal failure • Urinary retention Small intestine enteric system Skin (epidermis, dermis, Constipation fibroblasts, keratinocytes and hair follicles) • Analgesia • Anti-inflammation • Slow wound healing Skeletal muscle Immune system (lymphocytes, monocytes, macrophages and granulocytes) Immunosuppression b μ MOP 3 Parietal cortex μ Corpus callosum 2 Anterior cingulate μ Caudate 4 CPu 1 μ PFC μ 2 μ 4 μ Thalamus NAc Putamen μ Habenula 4 μ SN μ Periaqueductal μ μ VTA grey matter μ 7 5 μ Locus Septal area AMG coeruleus DG μ 8 6 Hypothalamus 3 HIPP Cerebellum Temporal μ cortex μ Pons μ 2 Brainstem • Pons δ-Opioid peptide K-Opioid peptide receptor in: • Medulla μ receptor in: • Cerebral cortex • Periaqueductal • Prefrontal cortex grey matter Medulla • Olfactory bulb • Temporal lobes • Locus coeruleus • AMG (including AMG) • Raphe magnus • Striatum (i.e. CPu) • Striatum (i.e. CPu) • Others • HIPP 2 • HIPP • Pontine nucleus Spinal cord • Hypothalamus • Spinal cord • Spinal cord • Dorsal root ganglion • Dorsal root ganglion • Cerebellum • Cerebellum www.nature.com/nrn REVIEWS ◀ Fig. 1 | Opioid actions throughout the body. a | The human body naturally synthetizes Neural progenitor proliferation. Although the majority opioids, which are used as neurotransmitters to regulate many vital functions. of NSPCs in the CNS undergo differentiation and finally Endogenous and exogenous opioids act through receptors found peripherally on lose their capacity to divide, actively dividing cells in nerve terminals innervating the adrenal glands, pancreas and gastrointestinal tract both embryonic and adult brains have nonetheless been and on immune, epidermal and dermal cells140,141, thus modulating steroid production, body weight via insulin secretion, opioid-induced constipation, inflammation and observed. As an indispensable process in the mainte- wound healing140,142–145. b | Opioids also activate centrally located receptors, such as nance of the stem pool and the generation of functional 17,26,27 the µ- opioid peptide receptor (MOP), that play a variety of roles in brain function. differentiated cells , the proliferation of NSPCs is a Control of food and drug intake is regulated by MOP in the prefrontal cortex (PFC) (1); crucial step in the regulation of neurogenesis (Fig. 3a). analgesia, slow breathing and relaxation can be induced by the activation of MOP in Thus far, the regulation of NSPC proliferation is con- the anterior cingulate, thalamus, brainstem nuclei, spinal cord and dorsal root ganglia sistently observed in response to many factors, including (2); sensory perception can be influenced by MOP in parietal and temporal cortices (3); MOP- targeting opioid drugs17. motivation, desire and associative learning involve stimulation of MOP in the nucleus The antiproliferative effects of opioids on embryonic accumbens (NAc), caudate–putamen (CPu) nuclei, ventral tegmental area (VTA) and NSPC proliferation were shown in the dorsal telenceph- substantia nigra (SN), key structures of the reward system (4); MOP is expressed in alon of the E15.5 embryonic mouse. Acute in utero mor- the amygdala (AMG), which is required for emotional conditioned learning and G2/M phase responses (5); MOP activation in the hippocampus (HIPP) can alter learning phine treatment resulted in a prolonged in and neurogenesis (6); and MOP is present in both the locus coeruleus, a structure both radial glial and basal progenitor cells, suggesting important in stress and drug withdrawal (7), and the cerebellum (8)2,6,61,141,146,147. a role of morphine in inhibiting cell cycle progression In general, the expression of opioid peptides in projection neurons, immune cells, or and embryonic neurogenesis in the developing cor- epidermal and dermal cells overlaps with the location of opioid receptor expression, tex28. More recently, it was found that acute morphine reflecting the autocrine, paracrine and endocrine mechanism of action of endogenous
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