The Journal of neuroscience : the official journal of the Society for Neuroscience
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Prevention of nerve injury-induced tactile, but not thermal, hypersensitivity is achieved by ipsilateral lesions of the dorsal columns or lidocaine microinjection into the nucleus gracilis (n. gracilis). These and other data support the possibility that tactile hyperresponsiveness after nerve injury may be selectively mediated by a low-threshold myelinated fiber pathway to the n. gracilis. Here we identify a transmitter that might selectively mediate such injury-induced tactile hypersensitivity. ⋯ Antagonist administration into the contralateral n. gracilis had no effect on injury-induced hypersensitivity. These data suggest the selective mediation of nerve injury-induced tactile hypersensitivity by upregulated NPY via large fiber input to n. gracilis. Selective reversal of injury-induced tactile allodynia by NPY receptor antagonists would have significant implications for human neuropathic conditions.
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Hypersensitivity resulting from nerve injury or morphine tolerance/hyperalgesia is predicted to involve similar cellular and molecular mechanisms. One expected but incompletely explored mechanism is the activation of central neuroimmune responses associated with these conditions. To begin to address this, we undertook three separate studies: First, we determined the acute antinociceptive action of morphine, the rate of development of opioid tolerance, and withdrawal-induced hyperalgesia/allodynia in nerve-injured and sham-operated rats using noxious (thermal and mechanical) and non-noxious (mechanical allodynia) behavioral paradigms. ⋯ This neuroimmune activation was further enhanced in nerve-injured rats after chronic morphine treatment. Spinal inhibition of proinflammatory cytokines restored acute morphine antinociception in nerve-injured rats and also significantly reversed the development of morphine tolerance and withdrawal-induced hyperalgesia and allodynia in nerve-injured or sham-operated rats. Targeting central cytokine production and glial activation may improve the effectiveness of morphine and reduce the incidence of morphine withdrawal-induced hyperalgesia and allodynia in neuropathic pain conditions.
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The tachykinin neuropeptide substance P and its receptor neurokinin 1 have been implicated in the regulation of many physiological and pathological processes, including the control of emotional behaviors. The present study examines mice with a targeted deletion of the Tac1 gene, which encodes the neuropeptides substance P and neurokinin A, in animal models relevant to depressive illness and anxiety. In depression-related paradigms, Tac1-deficient mice were more active in the Porsolt's forced-swimming test and the tail-suspension test, and they did not become hyperactive after bulbectomy. ⋯ They were more active and less affected by the light conditions in the central area of the open-field arena; they showed more social interactions in an aversive environment, they were more active in the open areas of an elevated zero-maze, and they had a reduced latency to feed in the Thatcher-Britton conflict paradigm. These results demonstrate that tachykinins are powerful mediators of depression-like or anxiety-related behaviors in mice. The tachykinin system therefore may play an important role in the regulation of emotional states and the development of anxiety disorders and depression.
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Damage-induced neuronal endopeptidase (DINE) is a novel metallopeptidase and is expressed in response to various neuronal injuries. The expression regulation of DINE mRNA in the dorsal root ganglia (DRGs) after sciatic nerve injury is examined. A substantial increase of DINE mRNA expression was observed in relatively small-sized DRG neurons after nerve injury. ⋯ Both LIF application and NGF deprivation additively enhanced DINE expression in vitro. These results suggest that DINE gene expression is regulated separately by both LIF and NGF deprivation, and this regulation pattern is similar to that of galanin gene expression. Because both DINE and galanin have a neuroprotective function, their simultaneous induction may provide more successful protection for injured sensory neurons.