Neuroscience
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Tolerance develops to the antinociceptive effects of morphine with repeated microinjections into the ventrolateral periaqueductal gray (PAG). This tolerance could be caused by adaptations within the PAG or anywhere along the descending pathway (rostral ventromedial medulla to spinal cord). If tolerance is caused by a change along the descending pathway, then tolerance should develop to direct activation of PAG output neurons. ⋯ Moreover, microinjection of bicuculline or kainate produced comparable antinociception in rats pretreated with these drugs and saline-treated control rats. These data demonstrate that repeated activation of ventrolateral PAG output neurons is not sufficient to produce tolerance. Thus, tolerance must be caused by a change in neurons preceding output neurons in this circuit, presumably opioid-sensitive GABAergic neurons.
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Fatty acid amide hydrolase (FAAH) catalyses hydrolysis of the endocannabinoid arachidonoylethanolamide ("anandamide") in vitro and regulates anandamide levels in the brain. In the cerebellar cortex, hippocampus and neocortex of the rat brain, FAAH is located in the somata and dendrites of neurons that are postsynaptic to axon fibers expressing the CB(1) cannabinoid receptor [Proc R Soc Lond B 265 (1998) 2081]. This complementary pattern of FAAH and CB(1) expression provided the basis for a hypothesis that endocannabinoids may function as retrograde signaling molecules at synapses in the brain [Proc R Soc Lond B 265 (1998) 2081; Phil Trans R Soc Lond 356 (2001) 381] and subsequent experimental studies have confirmed this [Science 296 (2002) 678]. ⋯ Here FAAH may nevertheless influence endocannabinoid signaling but more remotely. Finally, there are regions of the brain where FAAH-immunoreactive neurons and/or oligodendrocytes occur in the absence of CB(1)-immunoreactive fibers and here FAAH may be involved in regulation of signaling mediated by other endocannabinoid receptors or by receptors for other fatty acid amide signaling molecules. In conclusion, by comparing the distribution of FAAH and CB(1) in the mouse brain, we have provided a neuroanatomical framework for comparative analysis of the role of FAAH in regulation of the spatiotemporal dynamics of retrograde endocannabinoid signaling in different regions of the brain.
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The immunomodulatory thymic hormone thymulin has been shown previously to possess anti-inflammatory actions in the periphery. In this study, we have examined the effect of i.c.v. injections of either endotoxin (ET) or thymulin, in separate groups of conscious rats, on pain-related behavior and cytokine levels in different areas of the brain. Furthermore, we investigated the effect of pretreatment with either i.c.v. or i.p. injections of thymulin on endotoxin-induced hyperalgesia and the effect of pretreatment with i.c.v. thymulin on endotoxin-induced up-regulation of cytokine levels. ⋯ However, thymulin at different doses, when injected (i.c.v.), had no significant effect on pain related behavior. Pretreatment (i.c.v.) with thymulin (0.1, 0.5 and 1 microg in 5 microl saline) 20 min before endotoxin (i.c.v.) injection (1 microg in 5 microl saline) reduced, in a dose dependent manner, the endotoxin-induced hyperalgesia and exerted differential effects on the up-regulated levels of cytokines in different areas of the brain. The results provide behavioral and immunochemical characterization of a rat model for intracerebral inflammation and indicates a neuroprotective role for thymulin in the CNS.
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Remote areas undergoing delayed neuronal degeneration after focal brain ischemia display a preceding glial activation. The expression of proinflammatory cytokines there has not been examined so far. We examined the expression of TNFalpha in the thalamus and the substantia nigra pars reticulata (SNr) 1, 3 and 7 days after transient middle cerebral artery occlusion (MCAO) of the rat. ⋯ Neuronal degeneration was evident at day 14. Thus, in both areas, expression of TNFalpha precedes astrogliosis and neuronal degeneration. The different patterns of TNFalpha upregulation of the substantia nigra pars reticulata and the thalamus following middle cerebral artery occlusion may reflect different pathophysiological mechanisms leading to remote neuronal degeneration.
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Projection neurons in the ventral striatum, the accumbens nucleus and olfactory tubercle, were examined by combining the retrograde tracing method and immunocytochemistry with antibodies against C-terminals of the preprodynorphin (PPD), preproenkephalin (PPE), preprotachykinin A (PPTA) and preprotachykinin B (PPTB). When the retrograde tracer was injected into the ventral pallidum, about 60% and 40% of retrogradely labeled neurons in the accumbens nucleus were immunoreactive for PPD and PPE, respectively. In contrast, all accumbens nucleus neurons projecting to the ventral mesencephalic regions including the substantia nigra and ventral tegmental area were immunopositive for PPD but not for PPE. ⋯ A small population (2-12%) of accumbens neurons projecting to the ventral pallidum and mesencephalic regions displayed immunoreactivity for PPTB. Compared with the dorsal striatopallidal projection neurons that were reported to mostly express PPE, it was characteristic of the ventral striatum that only the smaller population (about 40%) of ventral striatopallidal projection neurons expressed PPE. This suggests that the ventral striatopallidal projection system is less specialized than the dorsal striatopallidal system in terms of peptide production, or that the ventral pallidum should be compared with a combined region of the globus pallidus and entopeduncular nucleus in the dorsal system.