Opioid receptors are G-protein coupled receptors that mediate the potent analgesic actions and addictive properties of morphine-derived compounds. Under physiological conditions, these receptors interact with endogenous opioid peptides to modulate pain-controlling pathways and circuits that modulate behaviors including mood and reward (2). opioid receptors interact with rapidly acting opioid drugs, such as heroin, to produce marked euphoria and behavioral reward. They are also primary targets of the slower and longer acting opioids, such as methadone and LAAM, 1 that represent the best current substitution therapeutics for opiate addiction (3).receptors desensitize after repeated stimulation by opioid agonists, in fashions that display similarities to desensitizing events noted for other G-protein coupled receptors. Agonistinduced receptor desensitization can be correlated with receptor phosphorylation. receptors display naloxone-reversible phosphorylation and desensitize after morphine or DAMGO treatments (1). Both of these agonist-induced events are insensitive to pretreatments with the protein kinase C inhibitor staurosporine, which inhibits phorbol ester-induced receptor phosphorylation and desensitization.Many opiates and opioid ligands can recognize receptors with high affinities. Plant-derived alkaloids, synthetic compounds of several classes, and endogenous opioid peptides can function as agonists, partial agonists, or antagonists with a range of abilities to induce or block induction of analgesia and euphoria. However, mutagenesis studies and studies with receptor chimeras support the idea that different receptor features could be involved in recognition of these different ligand classes (4 -6). Mutations that change naloxone from a full antagonist to a partial agonist can leave the intrinsic activity of opioid peptides unchanged, for example see Claude et al. (7). These differences raise the possibility that receptor occupancies by opioid drugs of different classes could alter the conformation of the receptor in distinct fashions. Some of these differences could render the receptor an improved or a worse substrate for kinases and phosphatases and thus directly confer different susceptibilities to phosphorylation or dephosphorylation. Alternatively, selective activation of different G-protein classes by different agonists could trigger different receptor phosphorylation and desensitization events.The current study thus investigates the effects of opioid ligands of various classes and varying intrinsic activities on receptor activation, phosphorylation, and desensitization using human receptors expressed in CHO cells (hCHO), and the receptors coexpressed in Xenopus oocytes with a G-protein linked K ϩ channel. The results support striking parallels between opioid efficacies in opening ion channels and inhibiting

Mitochondria are major sources of reactive oxygen species (ROS) within the cell and are especially vulnerable to oxidative stress. Oxidative damage to mitochondria results in disrupted mitochondrial function and cell death signaling, finally triggering diverse pathologies such as epilepsy, a common neurological disease characterized with aberrant electrical brain activity. Antioxidants are considered as promising neuroprotective strategies for epileptic condition via combating the deleterious effects of excessive ROS production in mitochondria. In this review, we provide a brief discussion of the role of mitochondrial oxidative stress in the pathophysiology of epilepsy and evidences that support neuroprotective roles of antioxidants targeting mitochondrial oxidative stress including mitochondria-targeted antioxidants, polyphenols, vitamins, thiols, and nuclear factor E2-related factor 2 (Nrf2) activators in epilepsy. We point out these antioxidative compounds as effectively protective approaches for improving prognosis. In addition, we specially propose that these antioxidants exert neuroprotection against epileptic impairment possibly by modulating cell death interactions, notably autophagy-apoptosis, and autophagy-ferroptosis crosstalk.

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