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  • In this study we reported that


    In this study, we reported that over-expressed endogenous central ET-1 exerted anti-allodynic and anti-hyperalgesic effects on SNL-induced NP for the first time. Furthermore, we showed that ETA-R mRNA Cy5 NHS ester together with the level of ET-1 was increased in the CNS up to 21days after SNL surgery in NTg mice, which corresponds with the situation in the peripheral nervous system (PNS) under pathological conditions of NP in normal animals in which the ETA-R and ET-1 message levels were both found to be up-regulated locally in a previous study (Klass et al., 2005). The same scenario was observed in GET-1 mice. These results demonstrated that ET-1 contributed significantly to the development of NP, probably via ETA-R, in both the central and peripheral nervous systems.
    Experimental methods
    Conflicts of interest/disclosures
    Source of funding The work described in this paper was substantially supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKU 763411).
    Introduction Opiates are frequently used in clinical settings for their analgesic properties and also abused as recreational drugs. It has long been known that neonates suffer deleterious effects as a result of maternal opiate use. Chronic exposure of the fetus or neonate during maternal opiate abuse leads to severe neurological and behavioral changes. On the other hand, there are several reported benefits to neonatal behavior and outcomes from opioid-based analgesia and anesthesia [1], [3], [25]. Currently, opioids are being widely used in neonates. However, chronic use of opioid analgesics results in tolerance and dependence. Iatrogenic opioid dependence was first reported in infants receiving fentanyl during extra corporeal membrane oxygenation (ECMO) [36]. Abrupt cessation of opiates leads to severe withdrawal syndrome which can significantly impact infant's hospital course. Management of these adverse effects may be a major challenge for the clinician. Recent animal studies have demonstrated that fetal rats and infant rat pups undergo opiate tolerance and physical dependence manifested as withdrawal, if the dams are exposed to opiates during pregnancy [5], [6], [17], [18], [38], [39], [41]. Morphine and other opioids act by binding and activating μ, κ, and δ opioid receptors. Opioid receptors are located on neuronal cells in the brain, spinal cord, myenteric plexus, peripheral nociceptors, and cell types including lympocytes, monocytes, skeletal muscle, and cardiac muscle [36]. Conformational changes in opioid receptors initiates signal transduction cascade due to activation of inhibitory G-proteins, Giα and Go. Gi-protein activation leads to inhibition of adenylyl cyclase (AC) enzyme, further leading to a decrease in intracellular cyclic adenosinemonophosphate (cAMP) levels [22], [37], [42]. Go-protein activation regulates an internally rectifying K+ channel and neuronal nitric oxide synthetase [37]. During opioid tolerance, opioid receptors are desensitized and cAMP pathways are upregulated, leading to an increase in second messengers such as AC and cAMP [4]. In addition to these second messengers, the βγ subunits liberated by activating heterotrimeric Gi- and Go-proteins can stimulate phospholipase C (PLC). Endothelin (ET-1) is a regulatory neuropeptide with widespread distribution in the central nervous system (CNS). ET-1 is produced by endothelial cells in the brain and non endothelial cells such as neurons, astrocytes, and glial cells [24]. ET receptors are found in the brain (cerebral cortex, hippocampus, cerebellum, hypothalamus, and medulla oblongata), spinal cord, and peripheral nociceptors. ET-1 activates G-protein-linked endothelin-A (ETA) and endothelin-B (ETB) receptors leading to activation of cellular signaling mechanisms. The diversity of actions of ET-1 may be explained in terms of the existence of several receptor subtypes and activation of different signal transduction pathways. Reports indicate that ET receptors are coupled with Gq and G12 family of G-proteins [20]. Activation of these pathways lead to activation of PLC which further activates protein kinase C (PKC) and increases intracellular Ca2+ [34]. Research also supports the evidence that ET receptors are linked to Gi- and Go-proteins [33], [34], [35].