Arimary afferent interactions: Analysis of calcitonin gene-related peptide-immunoreactive terminals in contact with unlabeled and GABA-immunoreactive profiles in the monkey dorsal horn

Hayes, Elizabeth S.; Carlton, Susan M.

doi:10.1016/0306-4522(92)90037-3

Cited by 61 publications

(35 citation statements)

References 115 publications

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“…For these reasons, we suggest that the stimulus-evoked release of CGRP occurs in a calcium-dependant manner from areas of LDCV exocytosis in a regulated fashion. This is consistent with electron microscopy studies (Alvarez et al, 1993;Hayes and Carlton, 1992) and functional investigations in the literature (Hingtgen and Vasko, 1994a;Kitamura et al, 2009;Matsuka et al, 2007). Because synaptic vesicles and LDCVs share similarities in the core aspects of the machinery involved in transmitter release (Edwards, 1998), our results showing the synaptic localization of CRMP-2 suggests that a CRMP-2-mediated increase in neurosecretion might occur via both classical and non-classical mechanisms.…”

Section: Crmp-2 Modulates Transmitter Releasesupporting

confidence: 91%

Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons

Xuan

Schmutzler

Brittain

et al. 2009

Journal of Cell Science

124

149

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Collapsin response mediator proteins (CRMPs) mediate signal transduction of neurite outgrowth and axonal guidance during neuronal development. Voltage-gated Ca2+ channels and interacting proteins are essential in neuronal signaling and synaptic transmission during this period. We recently identified the presynaptic N-type voltage-gated Ca2+ channel (Cav2.2) as a CRMP-2-interacting partner. Here, we investigated the effects of a functional association of CRMP-2 with Cav2.2 in sensory neurons. Cav2.2 colocalized with CRMP-2 at immature synapses and growth cones, in mature synapses and in cell bodies of dorsal root ganglion (DRG) neurons. Co-immunoprecipitation experiments showed that CRMP-2 associates with Cav2.2 from DRG lysates. Overexpression of CRMP-2 fused to enhanced green fluorescent protein (EGFP) in DRG neurons, via nucleofection, resulted in a significant increase in Cav2.2 current density compared with cells expressing EGFP. CRMP-2 manipulation changed the surface levels of Cav2.2. Because CRMP-2 is localized to synaptophysin-positive puncta in dense DRG cultures, we tested whether this CRMP-2-mediated alteration of Ca2+ currents culminated in changes in synaptic transmission. Following a brief high-K+-induced stimulation, these puncta became loaded with FM4-64 dye. In EGFP and neurons expressing CRMP-2–EGFP, similar densities of FM-loaded puncta were observed. Finally, CRMP-2 overexpression in DRG increased release of the immunoreactive neurotransmitter calcitonin gene-related peptide (iCGRP) by ∼70%, whereas siRNA targeting CRMP-2 significantly reduced release of iCGRP by ∼54% compared with control cultures. These findings support a novel role for CRMP-2 in the regulation of N-type Ca2+ channels and in transmitter release.

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Section: Crmp-2 Modulates Transmitter Releasesupporting

confidence: 91%

Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons

Xuan

Schmutzler

Brittain

et al. 2009

Journal of Cell Science

124

149

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“…Notably, GABAergic terminals make axo-axonic synapses with small diameter primary afferent terminals in the substantia gelatinosa (146)(147)(148)(149)(150), some of which may be unmyelinated (148,150) and contain SP (150, but see [151][152][153][154]. The proposed sources of the GABA are the terminals of 'islet cell' interneurons of laminae II and III in the rat spinal cord (155), although a contribution from descending GABAergic projections (156) cannot be ruled out.…”

Section: Is There Tonic Control Of Primary Afferent Neurotransmitter mentioning

confidence: 99%

Section: Is There Tonic Control Of Primary Afferent Neurotransmitter mentioning

confidence: 99%

“…The proposed sources of the GABA are the terminals of 'islet cell' interneurons of laminae II and III in the rat spinal cord (155), although a contribution from descending GABAergic projections (156) cannot be ruled out. There is also morphological evidence to suggest that small diameter primary afferents activate GABAergic interneurons of the superficial dorsal horn (149,150,152,157,158).Indeed, based on this evidence, it has been proposed that this circuit underlies a negative feedback mechanism that limits the further release of excitatory amino acids and/or peptides from the primary afferent nociceptor (100). Because the majority of NK-1 receptor-positive neurons in the spinal cord, including lamina I, are not GABA-immunoreactive (159), this pathway is likely to be indirect.…”

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confidence: 99%

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Presynaptic control of nociceptor signalling: Differential influence of Mu Opioid and GABAergic Systems

Riley

Trafton

Basbaum

2000

Pain Research and Management

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It is difficult to pick a topic to discuss that adequately honours Ron Melzack's many years of pain research. This is particularly problematic if one is cognizant of the tremendous emphasis that Ron puts on the distinction between pain and nociception. Indeed, the thread that binds so many of Ron's studies is that the complexity of the pain experience will not be understood if one exclusively concentrates on the processing of nociceptive messages at the level of the periphery or spinal cord. Ron always emphasized the importance of affective and cognitive components of the pain experience. These elements of the pain experience, so beautifully and memorably discussed in Melzack and Casey's (1) theoretical review, must always be included when this topic is addressed. Dr Allan Basbaum was a student of Ron's in an undergradu- The relative contribution of pre-and postsynaptic controls to the flow of nociceptive information at the level of the spinal cord has been one of Ron Melzack's longstanding interests and a key issue in the formulation of the gate control theory. The authors review their own studies, in which they monitored internalization of the neurokinin-1 receptor to examine specifically the action of two classically inhibitory systems -mu opioid and gamma-amino butyric acid (GABA) -on noxious stimulus-evoked tachykinin signalling in the rat spinal cord. Evidence that opioids and GABAergic controls operate differently on the central consequences of any noxious stimulus-induced substance P release is provided. Whereas at least 80% of the tachykinin signalling remained intact after even the highest concentration of spinal morphine or D-Ala2, NMe-phe4, Glyol5-enkephalin administration, spinal administration of the GABA B receptor agonist baclofen had a dramatic inhibitory effect. These findings are discussed in light of the disappointing clinical utility of baclofen and neurokinin-1 receptor antagonists to combat pain. Key Words: Gamma-amino butyric acid; Mu opioid; Neurokinin 1 receptors; Receptor internalization; Spinal cord; TachykininsCommande présynaptique de la transmission des signaux par les nocicepteurs : mécanisme d'action des opioïdes de type mu et du GABA Le rôle relatif des commandes pré-et postsynaptiques dans la transmission des signaux nociceptifs dans la moelle épinière, en plus de susciter l'intérêt soutenu de Ron Melzack, a constitué un pilier de la théorie du ‹‹ portillon ››. Les auteurs ont passé en revue leurs propres études dans lesquelles ils se sont penchés sur l'endocytose des récep-teurs de la neurokinine 1 afin d'étudier le mécanisme d'action de deux inhibiteurs classiques, les opioïdes de type mu et l'acide gammaaminobutyrique (GABA), sur la transmission de la tachykinine déclen-chée par un stimulus nocif dans la moelle épinière du rat. Ils ont recueilli des preuves selon lesquelles les opioïdes et le GABA agissent différemment sur les effets centraux de la libération de la substance P, provoquée par un stimulus nocif. Tandis qu'au moins 80 % de la transmission des signaux par la tac...

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“…One of the synaptic relationships of the primary afferent central endings to intrinsic neurons in the substantia gelatinosa (SG) has been reported to be postsynaptic contact with GABAergic neurites (McLaughlin et aL, 1975;Barber et aL, 1982;Magoul et a!., 1987;Todd and Lochhead, 1990). But recently, central endings were demonstrated to make presynaptic contacts with GABAergic dendrites with or without vesicles, though the latter dendrites show fewer postsynaptic contacts than the former (Carlton and Hayes, 1990;Hayes and Carlton, 1992). A survey of the synaptic relationships between nociceptive primary afferent central endings and intrinsic inhibitory interneurons in the SG is important for an understanding of the modulation of pain transmission.…”

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confidence: 99%

Relationship of Substance P-and CGRP-immunoreactive Central Endings of the Primary Afferent Neurons to GABAergic Interneurons in the Guinea Pig Substantia Gelatinosa

Hiura

Nasu

Ishizuka

1998

Okajimas Folia Anatomica Japonica

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Summary: The synaptic relationships between primary afferent central endings containing substance P (SP) and calcitonin gene-related peptide (CGRP) and GABAergic internenrons in the guinea pig substantia gelatinosa of the lumbar spinal dorsal horn were studied. The pre-embedding PAP method was used for detection of GABA and the post-embedding double immunogold labeling method for SP and CGRP detection. Immunogold particles specific for SP and CGRP were mainly localized separately or together in large synaptic vesicles devoid of dense cores. SP and CGRP immunoreactivity was separate or co-localized in small roundish, slender, sinuous or large scalloped (fan-like) terminals with closely packed round agranular synaptic vesides of various sizes and few large dense core vesides and mitochondria, which are thought to be capsaicin-sensitive primary afferent terminals. These SP-and CGRP-immunoreactive boutons make presynaptic or symmetric contacts with GABAergic dendrites and soma. These findings suggest that the central endings of nodceptive primary afferents transmit pain stimuli to intrinsic inhibitory internenrons, thereby modulating nodceptive information via a postsynaptic circuit.

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Arimary afferent interactions: Analysis of calcitonin gene-related peptide-immunoreactive terminals in contact with unlabeled and GABA-immunoreactive profiles in the monkey dorsal horn

Cited by 61 publications

References 115 publications

Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons

Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons

Presynaptic control of nociceptor signalling: Differential influence of Mu Opioid and GABAergic Systems

Relationship of Substance P-and CGRP-immunoreactive Central Endings of the Primary Afferent Neurons to GABAergic Interneurons in the Guinea Pig Substantia Gelatinosa

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