Brain research
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It is well known that prior experience to the elevated plus-maze increases the avoidance of rodents to the open arms and impairs the anxiolytic-like effect of benzodiazepines evaluated during a subsequent exposure to the maze, a phenomenon known as "one-trial tolerance". Centrally injected benzodiazepine drugs attenuate anxiety in some limbic structures, such as hypothalamus, amygdala and the midbrain periaqueductal gray (PAG). This study investigated the effects of intra-PAG infusions of midazolam (MDZ) in maze-naïve and maze-experienced mice. ⋯ The antiaversive effects of MDZ were completely blocked by prior injection of flumazenil which in turn did not alter any other behavioral measure. In maze-experienced mice, intra-PAG infusion of MDZ did not modify any behavioral measure. Taken together, present results corroborate previous studies demonstrating that GABA/benzodiazepine receptor complex located within the PAG plays a role on anxiety modulation in maze-naïve mice as well as indicate its involvement in the OTT phenomenon.
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Systemic (s.c.) injection in naïve mice of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors, e.g. 3-isobutyl-1-methylxanthine [(IBMX) or caffeine, 10 mg/kg] or the more specific cAMP-PDE inhibitor, rolipram (1 mug/kg), rapidly evokes thermal hyperalgesia (lasting >5 h). These effects appear to be mediated by enhanced excitatory opioid receptor signaling, as occurs during withdrawal in opioid-dependent mice. Cotreatment of these mice with ultra-low-dose naltrexone (NTX, 0.1 ng/kg-1 pg/kg, s.c.) results in prominent opioid analgesia (lasting >4 h) even when the dose of rolipram is reduced to 1 pg/kg. ⋯ Ultra-low-dose NTX, nor-BNI or beta-FNA selectively antagonizes high-efficacy excitatory (hyperalgesic) Gs-coupled opioid receptor-mediated signaling in naïve mice and results in rapid conversion to inhibitory (analgesic) Gi/Go-coupled opioid receptor-mediated signaling which normally requires activation by much higher doses of opioid agonists. Cotreatment with a low subanalgesic dose of kelatorphan, an inhibitor of multiple endogenous opioid peptide-degrading enzymes, stabilizes endogenous opioid agonists released by cAMP-PDE inhibitors, resulting in conversion of the hyperalgesia to analgesia without requiring selective blockade of excitatory opioid receptor signaling. The present study provides a novel pharmacologic paradigm that may facilitate development of valuable non-narcotic clinical analgesics utilizing cotreatment with ultra-low-dose rolipram plus ultra-low-dose NTX or related agents.
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The behavioral manifestations of autism, including reduced sociability (reduced tendency to seek social interaction), may be related to underdevelopment of the corpus callosum (CC). The BALB/cJ inbred mouse strain is a useful model system for testing the relationship between reduced sociability and CC underdevelopment. BALB/cJ mice show low levels of sociability, on average, but substantial intrastrain variability in sociability, as well as striking variability in CC development. ⋯ C57BL/6J mice showed consistently high levels of sociability and normal corpus callosum development. These results suggest that abnormal white matter structure is associated with deficits in sociability in BALB/cJ mice. Additional studies are warranted to elucidate the relationship between brain connectivity and sociability in this model system.
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Secondary ischemia (SI) following traumatic brain injury (TBI) increases damage to the brain in both animals and humans. The current study determined if SI after TBI alters the extent or duration of reduced energy production within the first 24 h post-injury and hippocampal cell loss at one week post-injury. Adult male rats were subjected to sham injury, lateral (LFPI) or central fluid percussion injury (CFPI) only, or to combined LFPI or CFPI with SI. ⋯ Cell counts in the CA1 region at 7 days post-injury revealed no significant neuronal cell loss after LFPI or CFPI alone. Significant neuronal cell loss was present only within the ipsilateral (p < 0.001) CA1 after LFPI+SI, but cell loss was bilateral (p < 0.001) after CFPI+SI. Thus, SI prolongs ATP reductions induced by LFPI and CFPI within the CA1 region and this SI-induced energy reduction appears to adversely affect regional neuronal viability.
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Comparative Study
An experimental model to measure excitatory and inhibitory pain mechanisms in humans.
Numerous approaches have been used to induce and measure experimental pain perception with the goal of better understanding excitatory and inhibitory pain mechanisms. In this study, the objective was to develop a simple experimental design which would enable us to elicit and measure multiple nociceptive mechanisms that have been reported to play a role in the development and persistency of chronic pain, such as temporal summation (TS) and diffuse noxious inhibitory control (DNIC). Eighty-three healthy subjects (42 men, 41 women) participated in this study where we examined pain perception of two tonic heat pain stimulation (thermode) separated by a 2 minute cold pressor test (CPT) (7 degrees C, 10 degrees C or 12 degrees C) which allowed us to activate DNIC. ⋯ Our experimental pain design allowed us to measure several excitatory and inhibitory pain mechanisms in one experimental session. We were able to separate the effect of DNIC on the peak pain and on TS. This method is simple, sensitive and can easily be used in different population of either healthy subjects or chronic pain patients.