Morphine

Morphine sulfate and other opiate/narcotic analgesics are the most effective treatments for acute and chronic severe pain. However, their clinical utility is often hampered by the development of analgesic tolerance as well as by de novo painful hypersensitivity to innocuous and noxious stimuli with such phenomena observed in both animal and human studies [73-75]. Human spermatozoa express 8-, k-, and m-opioid receptors. These receptors are located in different parts of the head, in the middle region, and in the tail of the sperm. The 8-receptor antagonist naltrindole significantly reduces progressive motility immediately after its addition. However, the 8-receptor agonist DPDPE has no significant effect. Finally, neither the k-receptor agonist U50488 nor its antagonist nor-binaltorphimine significantly affected the progressive motility of human spermatozoa.

Considerable evidence implicates nitroxidative stress in the development of pain of several etiologies and importantly in opiate antinociceptive tolerance, caused by the presence of superoxide, O2-^, nitric oxide, •NO, and more recently peroxynitrite or its protonated counterpart ONOOH that is the product of their interaction.

The mechanisms by which prolonged opiate exposure induces tolerance and hypersensitivity remain unclear, although a role for peroxynitrite-mediated nitroxi-dative stress has been identified [76]. Peroxynitrite is a potent proinflammatory and proapoptotic reactive species and a potent inducer of hyperalgesia (defined as augmented pain intensity in response to painful stimuli) [77-80] .

Considerable evidence over the years has supported the roles of 'NO and O2"• as precursors of peroxynitrite, in the development of morphine antinociceptive tolerance. Since the rate of interaction between 'NO and O2^ to form peroxynitrite is faster than the dismutation of O2-^ by superoxide dismutase, peroxynitrite formation from O2-^ and 'NO is the likely signaling molecule involved in antinociceptive tolerance as in pain of several etiologies [77, 80-83] ' Because studies have only recently begun to unravel the role of peroxynitrite in antinociceptive tolerance and pain, few data are available to help understand the molecular and biochemical pathways engaged by this nitrooxidative species. To date, we know that peroxynitrite contributes to peripheral and central sensitization by increasing production of proinflammatory cytokines, by activating PARP, and modulating the cyclooxygenase pathway to increase the production of proinflammatory and pronociceptive PGE' (activation of COX-1 and COX-2 and induction of COX-2) [80]. Peroxynitrite is also involved in neuroimmune activation, apoptosis and post-translational nitration and modification of key proteins known to be implicated in central and peripheral sensitization [82]. Additionally, nitroxidative species may be involved more subtly in central sensitization at least in part by sensitizing wide dynamic range neurons in the dorsal horn [84] ' Importantly for eventual clinical management, the peroxyni-trite decomposition catalysts evaluated to date apparently synergize with nonselec-tive COX-1/COX-2 inhibitors and selective COX-2 inhibitors, and do so at greatly reduced doses. This synergism should minimize the obvious side effects of either drug class when coadministered [82]. Considering the many molecular, biochemical, and pharmacological similarities between opiate-mediated antinociceptive tolerance and the hypersensitivity associated with chronic neuropathic pain, the broader implication of our proposed studies is that peroxynitrite is a viable therapeutic target in both disease states.

Morphine dependence can induce testis cell apoptosis, an increase in testis nitric oxide synthase positive cells, a decrease in calmodulin content and the activity of superoxide dismutase and glutathione superoxidase in the testis. NG-nitro-l-arginine has the curative effect on the morphine abstinent syndrome, protects testis cells against apoptosis and improves their involved biochemical indexes.

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