Glutamate receptors on postganglionic sympathetic axons

Carlton, Susan M.; Chung, Kyungsoon; Ding, Zenghui; Coggeshall, Richard E.

doi:10.1016/s0306-4522(97)00406-5

Cited by 38 publications

(27 citation statements)

References 25 publications

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“…Fibres in peripheral nerve supplying somatic tissues show NMDA receptors, but sympathetic fibres make up a significant proportion of the fibres examined in such studies. NMDA receptors were found on 36% of fibres in lumbar sympathetic rami [97], a proportion that increases after peripheral inflammation [98]; they are also present in vagus nerve fibres. Primary afferent fibres in both colon and urinary bladder stain immunohistochemically for NR1, and cell bodies in DRG labelled from colon have functional NMDA receptors [95].…”

Section: Peripheral Nmda Receptorsmentioning

confidence: 99%

NMDA Antagonists and Neuropathic Pain - Multiple Drug Targets and Multiple Uses

Chizh¹,

Headley²

2005

CPD

132

102

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NMDA (N-methyl-D-aspartate) receptors are one class of ionotropic receptor for the ubiquitous excitatory neurotransmitter L-glutamate. The receptor is made up of four protein subunits combined from a larger library of proteins, which gives this receptor a great deal of variability. This explains the large number of modulatory sites, a variety of sites at which antagonists can interact, and therefore a number of potential drug targets. Sensitivity of the NMDA ion channel to ambient levels of Mg++ gives it a voltage dependence that suits a function of responding to intense synaptic activation; the ability of the channel to admit Ca++ tends to trigger long-term processes. The receptor is thereby involved in long-term physiological processes such as learning and memory as well as in pathological processes such as neuropathic pain. Separating these functions therapeutically with NMDA antagonists has been a major difficulty, and has not yet been achieved with currently-available agents. This review summarises the preclinical rationale, based on animal models, and the clinical evidence on the use of NMDA antagonists in pain states. It also summarises the details of the receptor so as to explain the rationale for targeting either specific sites on the receptor, or exploiting anatomical differences in subtype expression, so as to provide the beneficial effects of NMDA receptor block with an improved side effect profile. In particular, agents that are selective for receptors that include the NR2B subunit preclinically have a substantially better profile for treating neuropathic pain than do current NMDA antagonists; some emerging clinical evidence supports this view.

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Section: Peripheral Nmda Receptorsmentioning

confidence: 99%

NMDA Antagonists and Neuropathic Pain - Multiple Drug Targets and Multiple Uses

Chizh¹,

Headley²

2005

CPD

132

102

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“…The first ionotropic receptors identified were found to activate chloride channels, but in recent years evidence has been gathered for presynaptic ionotropic receptors opening cationic channels (1). Most of the previous claims for the existence of presynaptic N-methyl-D-aspartate (NMDA) receptors were based either on observations indicating that antibodies against either the NR1 or the NR2 subunits label axons or synaptic boutons (2)(3)(4)(5)(6)(7)(8) or on functional studies suggesting a modulation by NMDA of transmitter release (9)(10)(11)(12)(13)(14). However, the characterization of NMDA receptors in presynaptic terminals has been complicated by the presence of NMDA receptors on the postsynaptic side (at most glutamatergic synapses) as well as on the somatodendritic compartment of the presynaptic neuron.…”

mentioning

confidence: 99%

Presynaptic N -methyl- d -aspartate receptors at the parallel fiber–Purkinje cell synapse

Casado

Dieudonné

Ascher

2000

Proc. Natl. Acad. Sci. U.S.A.

117

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At the cerebellar synapse between the parallel fibers (PFs) and the Purkinje cells in the cerebellum, we have found that application of N-methyl-D-aspartate (NMDA) reversibly depresses the postsynaptic current. We present evidence that this depression involves NMDA receptors located on the presynaptic axons and requires that the NMDA application be combined with action potentials in the PFs. Unexpectedly, unlike other modulations mediated by presynaptic receptors, the NMDA-induced inhibition does not involve a depression of transmitter release. Because it is blocked by both nitric oxide synthase and soluble guanylate cyclase inhibitors, we propose that it involves a trans-synaptic mechanism in which NO released by the PFs decreases the glutamate sensitivity of the Purkinje cell.A t many synapses transmission is modulated by presynaptic receptors that can be either metabotropic or ionotropic. The first ionotropic receptors identified were found to activate chloride channels, but in recent years evidence has been gathered for presynaptic ionotropic receptors opening cationic channels (1). Most of the previous claims for the existence of presynaptic N-methyl-D-aspartate (NMDA) receptors were based either on observations indicating that antibodies against either the NR1 or the NR2 subunits label axons or synaptic boutons (2-8) or on functional studies suggesting a modulation by NMDA of transmitter release (9-14). However, the characterization of NMDA receptors in presynaptic terminals has been complicated by the presence of NMDA receptors on the postsynaptic side (at most glutamatergic synapses) as well as on the somatodendritic compartment of the presynaptic neuron. In searching for a glutamatergic synapse at which it would be possible to study putative presynaptic NMDA receptors in relative isolation we chose the synapse between parallel fibers (PFs) and Purkinje cells (PCs) in the cerebellar cortex. At this synapse, immunolabeling has shown the presence on PFs of both NR1 (3) and NR2 (4) subunits, and after 2 weeks of age there are no functional NMDA receptors on the postsynaptic cell (15-17). Furthermore, the well-defined organization of the cerebellar cortex permits the stimulation of a homogeneous set of glutamatergic axons and the study of the synapse PF-PC with minimal interference from the somatodendritic receptors of the presynaptic granule cells. The starting point of our study was the observation that application of NMDA on cerebellar slices depresses the PF-PC excitatory postsynaptic current (EPSC). The analysis of this effect leads us to conclude that the NMDA receptors involved were those situated on the PFs. MethodsThin transverse cerebellar slices (300 m) were prepared following the method described by Llano et al. (16) from Wistar rats (aged 18-26 days). Slices were visualized by using a ϫ40 water-immersion objective (0.75 NA, Axioskop, Carl Zeiss) and infrared optics (illumination filter 750 Ϯ 50 nm; Sony chargecoupled device camera).All experiments were performed at room temperature (18-24°C). T...

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“…It was suggested that these peripherally distributed receptors play a role in the transmission of sensory signals to the central nervous system. 20,21 These findings are supported by the clinical report that intraplantar injections of glutamate or glutamate receptor agonists result in nociceptive behaviors similar to mechanical hyperalgesia and allodynia. These nociceptive behaviors can be attenuated by peripheral administration of NMDA and non-NMDA receptor antagonists.…”

Section: Discussionmentioning

confidence: 63%