Modulation of Thalamocingulate Nociceptive Transmission and Glutamate Secretion by Targeting P2×7 Receptor.

The complexity and diversity of pain signaling have led to obstacles for prominent treatments due to mechanisms that are not yet fully understood. Among adenosine triphosphate (ATP) receptors, P2×7 differs in many respects from P2×1-6, it plays a significant role in various inflammatory pain, but whether it plays a role in noninflammatory pain has not been widely discussed. In this study, we utilized major neuropharmacological methods to record the effects of manipulating P2×7 during nociceptive signal transmission in the thalamocingulate circuits.

Involvement of PX Receptors and BDNF in the Pathogenesis of Central Poststroke Pain.

Central pain is commonly found in patients with neurological complications that are associated with central nervous system insult, such as stroke. It can result directly from central nervous system injury. Impairments in sensory discrimination can make it challenging to differentiate central neuropathic pain from other types of pain or spasticity.

Targeting brain-derived neurotrophic factor in the medial thalamus for the treatment of central poststroke pain in a rodent model.

Approximately 7% to 10% of patients develop a chronic pain syndrome after stroke. This chronic pain condition is called central poststroke pain (CPSP). Recent studies have observed an abnormal increase in the secretion of brain-derived neurotrophic factor (BDNF) in spinal cord tissue after spinal cord injury.

Nociceptive transmission and modulation via P2X receptors in central pain syndrome.

Painful sensations are some of the most frequent complaints of patients who are admitted to local medical clinics. Persistent pain varies according to its causes, often resulting from local tissue damage or inflammation. Central somatosensory pathway lesions that are not adequately relieved can consequently cause central pain syndrome or central neuropathic pain.

A [14C]iodoantipyrine study of inter-regional correlations of neural substrates following central post-stroke pain in rats.

Background: Central pain syndrome is characterized by a combination of abnormal pain sensations, and pain medications often provide little or no relief. Accumulating animal and clinical studies have shown that impairments of the spinothalamic tract (STT) and thalamocingulate pathway causes somatosensory dysfunction in central post-stroke pain (CPSP), but the involvement of other neuronal circuitries in CPSP has not yet been systematically examined. The aim of the present study was to evaluate changes in brain activity and neuronal circuitry using [(14)C]iodoantipyrine (IAP) in an animal model of CPSP.

Targeting P(2)X(7) receptor for the treatment of central post-stroke pain in a rodent model.

Stroke is a leading cause of death and disability in industrialized countries. Approximately 8-14% of stroke survivors suffer from central post-stroke pain (CPSP) when hemorrhagic stroke occurs in lateral thalamic regions, which severely affects their quality of life. Because the mechanisms of CPSP are not well understood, effective treatments have not been developed.

APP anterograde transport requires Rab3A GTPase activity for assembly of the transport vesicle.

The amyloid precursor protein (APP) is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochemical composition of such a vesicle and the specific kinesin-1 motor responsible for transport are poorly defined. APP may be sequentially cleaved by beta- and gamma-secretases leading to accumulation of beta-amyloid (Abeta) peptides in brains of Alzheimer's disease patients, whereas cleavage of APP by alpha-secretases prevents Abeta generation. Here, we demonstrate by time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing the kinesin heavy chain isoform kinesin-1C, the small GTPase Rab3A, and a specific subset of presynaptic protein components.

5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice.

Although the mature enteric nervous system (ENS) has been shown to retain stem cells, enteric neurogenesis has not previously been demonstrated in adults. The relative number of enteric neurons in wild-type (WT) mice and those lacking 5-HT(4) receptors [knock-out (KO)] was found to be similar at birth; however, the abundance of ENS neurons increased during the first 4 months after birth in WT but not KO littermates. Enteric neurons subsequently decreased in both WT and KO but at 12 months were significantly more numerous in WT.

A functional P2X7 splice variant with an alternative transmembrane domain 1 escapes gene inactivation in P2X7 knock-out mice.

The ATP-activated P2X7 receptor channel is involved in immune function and inflammatory pain and represents an important drug target. Here we describe a new P2X7 splice variant (P2X7(k)), containing an alternative intracellular N terminus and first transmembrane domain encoded by a novel exon 1 in the rodent P2rx7 gene. Whole cell patch clamp recordings of the rat isoform expressed in HEK293 cells revealed an 8-fold higher sensitivity to the agonist Bz-ATP and much slower deactivation kinetics when compared with the P2X7(a) receptor.

Axonal accumulation of synaptic markers in APP transgenic Drosophila depends on the NPTY motif and is paralleled by defects in synaptic plasticity.

Alzheimer's disease (AD) is characterized by neurofibrillary tangles and extracellular plaques, which consist mainly of beta-amyloid derived from the beta-amyloid precursor protein (APP). An additional feature of AD is axonopathy, which might contribute to impairment of cognitive functions. Specifically, axonal transport defects have been reported in AD animal models, including mice and flies that overexpress APP and tau.

PAT1a modulates intracellular transport and processing of amyloid precursor protein (APP), APLP1, and APLP2.

Understanding the intracellular transport of the beta-amyloid precursor protein (APP) is a major key to elucidate the regulation of APP processing and thus beta-amyloid peptide generation in Alzheimer disease pathogenesis. APP and its two paralogues, APLP1 and APLP2 (APLPs), are processed in a very similar manner by the same protease activities. A putative candidate involved in APP transport is protein interacting with APP tail 1 (PAT1), which was reported to interact with the APP intracellular domain.