Neuroscience
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The hyaluronan receptor for hyaluronic acid-mediated motility (RHAMM) plays a role in cell migration and motility in many systems. Recent observations on the involvement of RHAMM in neurite motility in vitro suggest that it might also be important in axon outgrowth in situ. This was addressed directly by investigating both RHAMM expression in the rat CNS and the ability of anti-RHAMM reagents to interfere with tissue growth and axon outgrowth in intraocular brainstem transplants. ⋯ Treatment of grafts with anti-RHAMM antibody caused significant inhibition of tissue growth and axon outgrowth, as did a peptide corresponding to a hyaluronan binding domain of RHAMM. These agents had no such effects on transplants containing serotonergic and dopaminergic neurons. These results suggest that RHAMM, an extracellular matrix receptor previously shown to contribute to migratory and contact behavior of cells, may also be important in the growth and/or regenerative capacity of central noradrenergic fibers originating from the locus coeruleus.
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The effect of neuropeptide FF in the periaqueductal gray on pain behaviour was studied in rats with a chronic neuropathy induced by unilateral ligation of two spinal nerves. Neuropeptide FF produced in a non-monotonic fashion a significant attenuation of tactile allodynia. The antiallodynic effect was not significantly modulated by naloxone administered systemically or intracerebrally. ⋯ The results indicate that neuropeptide FF in the periaqueductal gray may produce a selective attenuation of tactile allodynia in neuropathic rats. This antiallodynic effect is at least partly independent of naloxone-sensitive opioid receptors. Furthermore, neuropeptide FF in the periaqueductal gray attenuates antinociception induced by intracerebrally but not systemically administered morphine.
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Although tumour necrosis factor alpha is said to play a key role in bacterial meningitis and other CNS diseases, the effects of this pro-inflammatory cytokine have only been studied in part and are incompletely understood. In a rat model, we investigated the effect of intracisternal injection of recombinant rat-specific tumour necrosis factor alpha (5, 35, 70 and 280 microg tumour necrosis factor alpha) (i) alone, (ii) combined with pneumococcal cell wall components, on regional cerebral blood flow, intracranial pressure, white blood cell count in the cerebrospinal fluid, and brain water content. ⋯ Combination of the lowest tumour necrosis factor alpha dose and a low dose pneumococcal cell wall preparation magnified the inflammatory effect of both. We conclude that intrathecally injected tumour necrosis factor alpha alone results in only minor inflammatory changes, whereas it dramatically augments experimental meningitis.
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Recent evidence indicates that neuropathic pain from partial peripheral nerve injury is maintained by electrophysiologically abnormal signals from injured sensory neurons. To gain an insight into the mechanisms underlying this electrophysiological abnormality, we examined the effects of S1 spinal nerve transection on the membrane properties of S1 dorsal root ganglion neurons one to two weeks after injury. This injury produced significant action potential broadening [40% (1 ms) in C-, 149% (1.5 ms) in A delta- and 84% (0.5 ms) in A alpha/beta-cells], which was primarily due to the enhancement of the "shoulder" appearing on the falling phase of the action potential in C- and A delta-cells and the emergence of a shoulder in A alpha/beta-cells, and significant cell-type specific changes in the time-course of the rising phase of the action potential; i.e. an increase in rise time (A delta: 35%, 0.15 ms; A alpha/beta: 13%, 0.04 ms) and a decrease in the maximal rate of rise (A delta: 17%, 77 V/s; A alpha/beta: 13%, 79 V/s). ⋯ The nerve injury-induced reduction of rheobase was not accompanied by related change in input resistance or threshold potential in any of the cell populations. The present results indicate that chronic peripheral axotomy of dorsal root ganglion neurons, which gives rise to neuropathic pain, produces profound changes in the action potential waveform of dorsal root ganglion neurons in a cell type-specific fashion. Furthermore, the results suggest that the axotomy increases the excitability of dorsal root ganglion neurons not by altering input resistance (i.e. leak conductance) or threshold potential, but by increasing apparent input resistance near the resting membrane potential in A-cells and decreasing the resting membrane potential in C-cells.
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Susceptibility to develop Parkinson's disease has been linked to abnormalities of P450 enzyme function. Multiple P450 enzymes are expressed in brain but the relationship of these to Parkinson's disease is unknown. We have investigated the expression of P450 enzymes in the rat substantia nigra and their co-localization in tyrosine hydroxylase-positive neurons and astrocytes. ⋯ At least two P450 enzymes are found in nigral dopamine containing cells and one, namely CYP2E1, is selectively localized to this cell population. CYP2E1 is a potent generator of free radicals which may contribute to nigral pathology in Parkinson's disease. The expression of CYP2E1 in dopaminergic neurons in substantia nigra raises the possibility of a causal association with Parkinson's disease.