Sex differences in the neurochemical mediation of swim stress-induced analgesia (SSIA) were examined in Swiss-Webster mice. Intact and gonadectomized adult mice of both sexes were tested for their analgesic response (hot-plate test) to 3 min of forced swimming in 15 degrees C and 20 degrees C water. SSIA resulting from 15 degrees C swim was previously shown to be naloxone-insensitive (i.e., non-opioid) whereas SSIA resulting from 20 degrees C swim produced an analgesia that was partially reversible by naloxone (i.e., mixed opioid/non-opioid). The non-opioid components of these SSIA paradigms were attenuated by the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). We now report that in males, but not females, dizocilpine (0.075 mg/kg, i.p.) and naloxone (10 mg/kg, i.p.) antagonized the non-opioid and opioid components of SSIA, respectively. After ovariectomy, females displayed a pattern of antagonism similar to males such that dizocilpine attenuated non-opioid SSIA, although naloxone remained ineffective in antagonizing 20 degrees C SSIA. Thus, SSIA in intact females was neither opioid- nor NMDA-mediated, yet it was of similar magnitude to the SSIA displayed by intact males. In separate experiments, estrogen replacement (estrogen benzoate; 5.0 micrograms/day, i.p.) administered to ovariectomized mice over a 6-8 day period reinstated the dizocilpine-insensitivity of 15 degrees C SSIA characteristic of intact females. However, a similar estrogen regimen administered to both intact and castrated males did not compromise the sensitivity to dizocilpine previously noted in male mice.(ABSTRACT TRUNCATED AT 250 WORDS)

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Release of the excitatory neurotransmitter glutamate and the excessive stimulation of N-methyl-Daspartate (NMDA)-type glutamate receptors is thought to be responsible for much of the neuronal death that occurs following focal hypoxia-ischemia in the central nervous system. Our laboratory has identified endogenous sulfated steroids that potentiate or inhibit NMDA-induced currents. Here we report that 3␣-ol-5␤-pregnan-20-one hemisuccinate (3␣5␤HS), a synthetic homologue of naturally occurring pregnanolone sulfate, inhibits NMDA-induced currents and cell death in primary cultures of rat hippocampal neurons. 3␣5␤HS exhibits sedative, anticonvulsant, and analgesic properties consistent with an action at NMDA-type glutamate receptors. Intravenous administration of 3␣5␤HS to rats (at a nonsedating dose) following focal cerebral ischemia induced by middle cerebral artery occlusion significantly reduces cortical and subcortical infarct size. The in vitro and in vivo neuroprotective effects of 3␣5␤HS demonstrate that this steroid represents a new class of potentially useful therapeutic agents for the treatment of stroke and certain neurodegenerative diseases that involve over activation of NMDA receptors.Exposure of neurons to the excitatory neurotransmitter glutamate causes an increase in the concentration of intracellular free Ca 2ϩ (1) and initiates the process of excitotoxic cell death (2). There are at least three pharmacologically distinct ionotropic glutamate receptors that differ in their sensitivity to the selective agonists N-methyl-D-aspartate (NMDA), ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate. Whereas excessive activation of NMDA, AMPA, or kainate receptors results in neurotoxicity, specific inhibition of NMDA receptors is sufficient to attenuate most of the neuronal death that develops after in vitro hypoxia, exposure to glutamate, in vivo ischemia, or hypoglycemia (3). As Ca 2ϩ passes through the NMDA receptor operated ion channel, it is believed that this receptor subserves a crucial role in mediating excitotoxicity. Therefore, it has been proposed that over activation of NMDA receptors may be an obligatory phase preceding neuronal death that occurs following focal cerebral ischemia induced stroke in humans.Neuroactive steroids have been shown to directly modulate excitatory and inhibitory amino acid receptor function (4-7). Therefore the possibility is raised that certain steroids might be useful neuroprotective agents. The endogenous neurosteroid pregnenolone sulfate probably acts as a positive allosteric modulator of the NMDA receptor by enhancing NMDAinduced inward currents and the subsequent rise in cytoplasmic free calcium (8, 9), whereas 3␣-ol-5␤-pregnan-20-one sulfate (3␣5␤S) is a negative modulator of NMDA-induced currents (6) and inhibits NMDA-stimulated increases in intracellular calcium (10). The present study examines the in vitro and in vivo neuroprotective activity of 3␣-ol-5␤-pregnan-20-one hemisuccinate (3␣5␤HS) ( Fig. 1; a synthetic analog of the endogenou...

The present review summarizes the current state of knowledge about the genetics of pain-related phenomena and illustrates the scope and power of genetic approaches to the study of pain. We

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