Neuroscience
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The cloning of the receptor for capsaicin, vanilloid receptor 1, has shown it to be non-selective cation channel with a high calcium permeability which can be opened by noxious heat as well as capsaicin. Here we compare the calcium signals produced by native and recombinant capsaicin receptors when activated by either heat or capsaicin by imaging intracellular calcium levels ([Ca2+](i)) in rat dorsal root ganglion neurons and Chinese hamster ovary cells transfected with the rat vanilloid receptor, vanilloid receptor 1. Vanilloid receptor 1 transfected cells and a subset of dorsal root ganglion neurons responded to both capsaicin and to heating to 50 degrees C with rapid, substantial and reversible rises in [Ca2+](i). ⋯ In vanilloid receptor 1 transfected cells, Ruthenium Red (10microM) blocked responses to both capsaicin and heat. These results demonstrate that imaging of [Ca2+](i) can identify dorsal root ganglion neurons which are responsive to both heat and capsaicin. They show that heat and capsaicin responses mediated by native and recombinant capsaicin receptors are similar with respect to the characteristics and pharmacology examined, suggesting that expression of recombinant vanilloid receptor 1 in cell lines accurately reproduces the properties of the native receptor.
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Formalin injected subcutaneously into the paw is a widely used model of pain. This procedure evokes a short-lasting period of flinching (phase 1) and a long-lasting period of intense flinching (phase 2) following a very short period of quiescence. Phase 2 has been extensively used to support the involvement of central (spinal cord) sensitization in inflammatory hyperalgesia. ⋯ Pretreatment of the paws with a mast cell stabilizer, sodium cromoglycate, significantly reduced the second phase of the formalin injection model. From these results we suggest that phases 1 and 2 of the formalin test are dependent upon the ongoing afferent input. Furthermore, while histamine H1 participates in both phases, 5-hydroxytryptamine(4/3) participates in phase 1 and 5-hydroxytryptamine(1A) in phase 2.
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The expression of interleukin-1beta and tumor necrosis factor has previously been shown to be up-regulated in the spinal cord of several rat mononeuropathy models. This present study was undertaken to determine whether blocking the action of central interleukin-1beta and tumor necrosis factor attenuates mechanical allodynia in a gender-specific manner in a rodent L5 spinal nerve transection model of neuropathic pain, and whether this inhibition occurs via down-regulation of the central cytokine cascade or blockade of glial activation. Interleukin-1 receptor antagonist or soluble tumor necrosis factor receptor was administered intrathecally via lumbar puncture to male Holtzman rats in a preventative pain strategy, in which therapy was initiated 1h prior to surgery. ⋯ At days 3 and 7 post-transection, animals receiving daily interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibited significantly less interleukin-6, but not interleukin-1beta, in the L5 spinal cord compared to vehicle-treated animals. In an existing pain paradigm, in which treatment was initiated on day 7 post-transection, interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor attenuated mechanical allodynia (P<0.05) in male rats. These findings further support a role for central interleukin-1beta and tumor necrosis factor in the development and maintenance of neuropathic pain through induction of a proinflammatory cytokine cascade.
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The periaqueductal grey (PAG) region of the brainstem is a known modulator of somatic pain transmission. Migraine is likely to be due to episodic brain dysfunction in pathways involved in the control of pain and other sensory modalities, such as light and sound. To investigate the influence of the PAG on pain transmission from intracranial structures, we examined spinal trigeminal neuronal activity in response to PAG stimulation in a model of trigeminovascular nociception in the cat. ⋯ This effect could be seen both ipsilateral and contralateral to the side of PAG stimulation and was well localised to the ventrolateral PAG. These data demonstrate that a role of the PAG is to inhibit afferent trigeminal nociceptive traffic. Considered with neurosurgical and human functional imaging studies, these data support the notion that brainstem dysfunction might lead to disinhibition of trigeminal afferents and be important in the pain process of migraines.
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The cholinergic neurons which originate in the mesopontine tegmentum and innervate the midbrain ventral tegmental area have been proposed to play a key role in intracranial self-stimulation reward. This mesopontine area also contains GABA neurons. Detailed information is still lacking, however, about the relationship of cholinergic and GABAergic neurons in this region to self-stimulation reward. ⋯ One hour of self-stimulation significantly increased acetylcholine efflux from this terminal area. These results indicate that intracranial self-stimulation of the medial forebrain bundle may increase acetylcholine release without affecting expression of Fos in cholinergic neurons, while the same stimulation may induce Fos expression in GABAergic neurons of the mesopontine tegmentum. GABAergic as well as cholinergic neurons in this area appear to be activated by self-stimulation reward in the medial forebrain bundle.