Pathophysiology of parkinsonism due to hydrocephalus.

We report a patient with hydrocephalus who developed levodopa responsive parkinsonism and severe bradyphrenia associated with shunt malfunction and revision. Magnetic resonance imaging revealed periaqueductal edema involving medial substantia nigra. [18F]dopa positron emission tomography demonstrated reduced uptake in the caudate and putamen with relative sparing of the posterior putamen. Hydrocephalus associated with shunt malfunction can cause a distinct parkinsonian syndrome with greater dysfunction of projections from the medial substantia nigra to anterior striatum than in idiopathic Parkinson's disease.

Dopamine reuptake inhibition in the rostral agranular insular cortex produces antinociception.

We provide evidence for an antinociceptive effect of dopamine in the rat cerebral cortex that is mediated through descending nociceptive inhibition of spinal neurons. Injection of the dopamine reuptake inhibitor GBR-12935 in the rostral agranular insular cortex (RAIC), a cortical area that receives a dense dopaminergic projection and is involved in descending antinociception (Burkey et al.,1996), resulted in dose-dependent inhibition of formalin-induced nociceptive behavior, without any alteration of motor function. Injection of the dopamine reuptake inhibitor in the surrounding cortical areas had no effect on nociceptive behaviors. GBR-12935 also produced a reduction in noxious stimulus-induced c-fos expression in nociceptive areas of the spinal dorsal horn, suggesting that dopamine in the RAIC acts in part through descending antinociception. Electrophysiological recording from single wide dynamic range-type spinal dorsal horn neurons confirmed the descending nociceptive inhibitory effect. GBR-12935 in the RAIC significantly reduced neuronal responses evoked by noxious thermal stimulation of the skin, an effect that was reversed by local administration of the selective D1 receptor antagonist SCH-23390. Finally, administration of SCH-23390 alone in the RAIC decreased paw withdrawal latencies from noxious heat, suggesting that dopamine acts tonically in the cortex to inhibit nociception.

Reorganization of the spinal dorsal horn in models of chronic pain: correlation with behaviour.

Central reorganization is known to occur in chronic pain models resulting from peripheral injury. Systematic analysis of anatomical and behavioural changes and a comparison of these changes between different models over an extended time course has not been reported. We address this issue by quantifying alterations in markers known to be associated with central reorganization in three models of peripheral injury: complete Freund's adjuvant induced inflammation of the hindpaw, chronic constriction of the sciatic nerve, and tight ligation of the sciatic nerve. Hyperalgesic behaviour to thermal and mechanical stimuli was quantified at four, seven, 14, 28 days post-injury. Distribution and immunodensity changes of the mu-opioid receptor, the neurokinin-1 receptor, and brain nitric oxide synthase distribution were assessed in the superficial dorsal horn, laminae I-II, of the lumbar spinal cord of the rat. Reorganization and behavioural changes were quantified as a per cent change (ipsilateral versus contralateral) and examined together over the duration of the experiment. Chronic constriction injury and inflammation both produced hyperalgesic behaviour in the hindpaw ipsilateral to injury. Decreases in thermal and mechanical withdrawal latencies were maximal at day 4. Complete Freund's adjuvant-treated animals displayed a 25.5%+/-3.8% decline in thermal withdrawal latency and 84.1%+/-8.0% decline in mechanical withdrawal latency. Chronic constriction of the sciatic nerve resulted in an decrease in thermal and mechanical withdrawal latencies, 27.9%+/-3.3%, 90.5%+/-4.4%, respectively. Tight ligation of the sciatic nerve resulted in early increases in the latency of withdrawal that were maximal at seven days 40.7%+/-8.4% for thermal stimulus and at four days 417%+/-5.8% for mechanical stimulus, consistent with deafferentation. The greatest changes in immunolabelling were always found at L4-L5 spinal level, corresponding to the entry zone of sciatic afferents. Mu-opioid receptor immunodensities increased in the dorsal horn ipsilateral to the treated side up to a maximum of 38.3%+/-5.6% at day 7 with inflammation and up to 26.3%+/-3.2%, at day 14 with chronic constriction injury. Mu-opioid receptor immunodensities decreased maximally by 20.0%+/-2.1% at day 4 in the tight ligature model. Significant differences in mu-opioid receptor immunolabelling persisted at day 28 for neuropathic models, at which time there was an absence of significant hyperalgesic behaviour in any group. The number of brain nitric oxide synthase-positive cells decreased at seven days by a maximum of 45.3%+/-5.1% and 59.0%+/-5.2%, respectively, in animals with chronic constriction injury or tight ligature. This decline in immunolabelled brain nitric oxide synthase cells in the dorsal horn ipsilateral to injury persisted at day 28. No significant alteration in brain nitric oxide synthase immunolabelling was found in association with inflammation of the hindpaw. Inducible nitric oxide synthase was not detected in the dorsal horn at any time during the experiment in either tissue of treated or control rats. Neurokinin-1 receptor immunodensity consistently increased ipsilateral to injury irrespective of the type of injury, and, of the three markers, paralleled behaviour most closely. Changes were maximal for inflammation at four days (75.2%+/-9.3%), for chronic constriction injury at four days (85.1%+/-14.6%) and for tight ligature at 14 days (85.7%+/-11.4%). Comparison of behavioural and anatomical data demonstrates that the peak hyperalgesia is concomitant with the greatest increase in neurokinin-1 receptor immunodensity ipsilateral to the injury. The increase in mu-opioid receptor immunodensity parallels behaviour but with a delayed time course, peaking as hyperalgesia abates, except in the case of tight ligature animals where the decrease in immunolabelling appears permanent. (ABSTRACT TRUNCATED)

Transneuronal labeling of a nociceptive pathway, the spino-(trigemino-)parabrachio-amygdaloid, in the rat.

Transneuronal tracing of a nociceptive pathway, the spino-(trigemino)-parabrachio-amygdaloid pathway, was performed using an alpha-herpes virus, the Bartha strain of pseudorabies virus (PRV). Microinjection of PRV into the central nucleus of the amygdala (Ce) resulted in progressive retrograde and transneuronal infection of a multisynaptic circuit involving neurons in the brainstem and spinal cord as detected immunocytochemically. At short survival (26 hr), retrogradely labeled neurons were concentrated in the external lateral nucleus of the parabrachial complex (elPB) but were absent from both the trigeminal nucleus caudalis (TNC) and the spinal cord. At longer survivals (52 hr), labeled cells were present in lamina I of both the TNC and spinal dorsal horn. Retrograde labeling from the Ce with Fluoro-gold demonstrated that elPB neurons have long dendrites extending laterally into the terminal field of spinal and trigeminal afferents, where transneuronal passage of PRV to these afferents could occur. Even longer survivals (76 hr) resulted in a columnar pattern of cell labeling in the TNC and spinal dorsal horn that extended from lamina I into lamina II. At this longest survival, primary sensory neurons became infected. Bilateral excitotoxic lesions of the elPB blocked almost all viral passage from the Ce to superficial laminae of the TNC and spinal dorsal horn. These results demonstrate that nociceptive input to the amygdala is relayed from neurons in lamina I through the elPB. We propose that this modular arrangement of lamina I and II neurons may provide the basis for spinal processing of peripheral input to the amygdala.

An opioidergic cortical antinociception triggering site in the agranular insular cortex of the rat that contributes to morphine antinociception.

We report an anatomically defined opioid-responsive site in the rostral agranular insular cortex (RAIC) of the rat and characterize the antinociception produced by morphine acting within this region. Immunohistochemistry for the mu-opioid receptor identified a discretely localized cluster of densely labeled dendrite-like processes in the agranular insular cortex. The antinociceptive effect of morphine microinjected unilaterally into this area was evaluated using the formalin test. Antinociception was observed in both ipsilateral and contralateral hindpaws. Local pretreatment with naltrexone in the RAIC blocked the antinociception of local morphine injection, confirming that morphine was acting at an opioid receptor. Unilateral injection of naloxone methiodide into the RAIC reversed the behavioral antinociception of systemic morphine bilaterally in the formalin test. Evidence for a descending inhibitory mechanism acting on spinal nociceptive neurons was obtained by monitoring noxious stimulus-induced c-fos expression in rats having undergone formalin testing and by electrophysiological recording of single units in the lumbar dorsal horn after localized application of morphine into the RAIC. A significant reduction in the number of Fos-like immunoreactive neurons was found ipsilateral to the formalin stimulus in nociresponsive areas of the dorsal horn after on-site injections of morphine into the RAIC. Electrophysiological recording of nociresponsive dorsal horn neurons demonstrated a naloxone-reversible reduction in noxious thermal stimulus-evoked firing after morphine injection into this same area. These results suggest that the RAIC contributes to opioid-receptor-mediated antinociception after either local or systemic morphine administration and that these effects may be associated with an increased descending inhibition of dorsal horn neurons.