Endothelin ET is a regulatory

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 neomycin sulfate sale 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]. Nociceptive and hyperalgesic actions of ET-1 are produced through ETA and ETB receptors. Previous reports indicate that ETA receptor antagonists in peripheral tissues are effective in inhibiting ET-1 induced hyperalgesia, and attenuation of neuropathic pain in rats [16]. Studies have also shown that stimulation of ETB receptors by ETB receptor selective agonist, IRL1620, inhibits ET-1 induced pain and this may be through a peripheral opioid receptor-mediated action on nociceptors in the skin [21]. Although peripheral ETB receptor agonist, IRL1620, has been shown to be involved in analgesia through opioid receptors, however, centrally administered ETB receptor agonists did not produce any effect on morphine analgesia [8]. We have demonstrated the involvement of central ET receptors in morphine analgesia and tolerance. In adult rats it was found that ETA receptor antagonists (BMS182874 and BQ123) significantly potentiated the analgesic response induced by morphine [10]. It was also found that ETA receptor antagonists prevent and reverse development of tolerance to morphine analgesia [9]. Studies conducted in neonatal rats showed involvement of ET receptors in morphine tolerance [31]. It was found that ET receptor antagonists did not act on opioid receptors directly, but modulated the action of morphine by acting through G-proteins [31]. In morphine tolerant neonatal rats, morphine and ET-1 induced G-protein stimulation was significantly reduced while ETA receptor antagonist induced G-protein stimulation was enhanced compared to control. No study has been conducted to determine the involvement of ET in neonatal morphine withdrawal. The present study was therefore planned to determine the effect of ETA receptor antagonist and ETB receptor agonist on G-protein stimulation in the brain of neonatal rats undergoing morphine withdrawal.
Materials and methods
Discussion