Progress in neurobiology
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Progress in neurobiology · Apr 1999
ReviewNociceptin/orphanin FQ: role in nociceptive information processing.
Recently, opioid receptor like1 (ORL1) receptor was identified. The ORL1 receptor is a G protein coupled receptor and the sequence of the ORL1 receptor is closely related to that of the opioid receptors. Nociceptin/orphanin FQ has been identified as a potent endogenous agonist of the ORL1 receptor and the sequence of nociceptin/orphanin FQ is closely related to that of dynorphin A. ⋯ Intracerebroventricular (i.c.v.) injection of nociceptin/orphanin FQ produced hyperalgesia and allodynia and antagonized morphine analgesia. On the other hand, intrathecal injection of low dose nociceptin/orphanin FQ produces allodynia, but high dose of nociceptin/orphanin FQ produces an analgesic effect. Although we do not fully understand the mechanisms that produce the difference between the effect of i.c.v. injection of nociceptin/orphanin FQ and that of intrathecal injection of nociceptin/orphanin FQ, we believe that spinal ORL1 receptor may be the next receptor which should be targeted by drugs designed for the treatment of pain.
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Progress in neurobiology · Feb 1999
ReviewActivity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system.
This review primarily discusses work that has been performed in our laboratories and that of our direct collaborators and therefore does not represent an exhaustive review of the current literature. Our aim is to further discuss the role that gene expression plays in neuronal plasticity and pathology. In the first part of this review we examine activity-dependent changes in the expression of inducible transcription factors (ITFs) and neurotrophins with long-term potentiation (LTP) and kindling. ⋯ We also discuss whether loss of retrograde transport of neurotrophic factors such as nerve growth factor following nerve transection triggers the selective and prolonged expression of c-Jun in axotomized neurons and whether c-Jun is responsible for regeneration or degeneration of these axotomized neurons. In the last section we further examine the role that gene expression may play in memory formation, epileptogenesis and neuronal degeneration, lastly speculating whether the expression of various growth factors after brain injury represents an endogenous neuroprotective response of the brain to injury. Here we discuss our results which show that pharmacological enhancement of this response with exogenous application of IGF-1 or TGF-beta reduces neuronal loss after brain injury.
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The highly disagreeable sensation of pain results from an extraordinarily complex and interactive series of mechanisms integrated at all levels of the neuroaxis, from the periphery, via the dorsal horn to higher cerebral structures. Pain is usually elicited by the activation of specific nociceptors ('nociceptive pain'). However, it may also result from injury to sensory fibres, or from damage to the CNS itself ('neuropathic pain'). ⋯ This neuronal framework is then exploited for a consideration of peripheral, spinal and supraspinal mechanisms involved in the induction of pain by stimulation of peripheral nociceptors, by peripheral nerve injury and by damage to the CNS itself. Finally, a hypothesis is forwarded that neurotrophins may play an important role in central, adaptive mechanisms modulating nociception. An improved understanding of the origins of pain should facilitate the development of novel strategies for its more effective treatment.
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Progress in neurobiology · Apr 1998
ReviewPharmacology of glutamate receptor antagonists in the kindling model of epilepsy.
It is widely accepted that excitatory amino acid transmitters such as glutamate are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using NMDA receptors, but more recent evidence indicates potential roles for ionotropic non-NMDA (AMPA/kainate) and metabotropic glutamate receptors as well. Based on the role of glutamate in the development and expression of seizures, antagonism of glutamate receptors has long been thought to provide a rational strategy in the search for new, effective anticonvulsant drugs. ⋯ In contrast, ionotropic non-NMDA receptor antagonists exert potent anticonvulsant effects on both initiation and propagation of kindled seizures. This effect can be markedly potentiated by combination with low doses of NMDA antagonists, suggesting that an optimal treatment of focal and secondarily generalized seizures may require combined use of both non-NMDA and NMDA antagonists. Given the promising results obtained with novel AMPA/kainate antagonists and glycine/NMDA partial agonists in the kindling model, the hope for soon having potentially useful glutamate antagonists for use in epileptic patients is increasing.
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Progress in neurobiology · Jul 1997
ReviewMetaplasticity: a new vista across the field of synaptic plasticity.
Over the past 20 years there has been an increasing understanding of the properties and mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic efficacy, putative learning and memory mechanisms in the mammalian brain. More recently, however, it has become apparent that synaptic activity can also elicit persistent neuronal responses not manifest as changes in synaptic strength. Some of these changes may nonetheless modify the ability of synapses to undergo strength changes in response to subsequent episodes of synaptic activity. ⋯ The mechanisms underlying such phenomena remain to be fully characterized, although some likely possibilities are an altered N-methyl-D-aspartate receptor function, altered calcium buffering, altered states of kinases or phosphatases, and a priming of protein synthesis machinery. While some details vary, experimentally observed metaplasticity bears some similarity to the "sliding threshold" feature of the Bienenstock, Cooper and Munro model of experience-dependent synaptic plasticity. Metaplasticity may serve several functions including (1) providing a way for synapses to integrate a response across temporally spaced episodes of synaptic activity and (2) keeping synapses within a dynamic functional range, and thus preventing them from entering states of saturated LTP or LTD.