Modification of classical neurochemical markers in identified primary afferent neurons with Aβ‐, Aδ‐, and C‐fibers after chronic constriction injury in mice

Ruscheweyh, Ruth; Forsthuber, Liesbeth; Schoffnegger, Doris; Sandkühler, Jürgen

doi:10.1002/cne.21311

Cited by 165 publications

(172 citation statements)

References 52 publications

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“…Anti-NF200 specifically recognizes the neurofilaments with a molecular weight of 200 kDa on immunoblots from rat spinal cord and does not crossreact with other intermediate filament proteins (manufacturer's technical information). Anti-NF200 has been established as a marker of DRG neurons having (Hammond et al, 2004;Lawson and Waddell, 1991;Ruscheweyh et al, 2007). The pattern of staining obtained in our experiments with this antibody was similar to that previously reported for DRG from other studies (Chao et al, 2008;Keast et al, 2010;Ruscheweyh et al, 2007;Schumacher et al, 1999).…”

Section: Primary Antibody Characterizationsupporting

confidence: 88%

Morphological and functional characterization of cholinergic interneurons in the dorsal horn of the mouse spinal cord

Mesnage

Gaillard

Godin

et al. 2011

J of Comparative Neurology

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Endogenous acetylcholine is an important modulator of sensory processing, especially at the spinal level, where nociceptive (pain-related) stimuli enter the central nervous system and are integrated before being relayed to the brain. To decipher the organization of the local cholinergic circuitry in the spinal dorsal horn, we used transgenic mice expressing enchanced green fluorescent protein specifically in cholinergic neurons (ChAT::EGFP) and characterized the morphology, neurochemistry, and firing properties of the sparse population of cholinergic interneurons in this area. Three-dimensional reconstruction of lamina III ChAT::EGFP neurons based either on their intrinsic fluorescence or on intracellular labeling in live tissue demonstrated that these neurons have long and thin processes that grow preferentially in the dorsal direction. Their dendrites and axon are highly elongated in the rostrocaudal direction, beyond the limits of a single spinal segment. These unique morphological features suggest that dorsal horn cholinergic interneurons are the main contributors to the plexus of cholinergic processes located in lamina IIi, just dorsal to their cell bodies. In addition, immunostainings demonstrated that dorsal horn cholinergic interneurons in the mouse are γ-aminobutyric acidergic and express nitric oxide synthase, as in rats. Finally, electrophysiological recordings from these neurons in spinal cord slices demonstrate that two-thirds of them have a repetitive spiking pattern with frequent rebound spikes following hyperpolarization. Altogether our results indicate that, although they are rare, the morphological and functional features of cholinergic neurons enable them to collect segmental information in superficial layers of the dorsal horn and to modulate it over several segments.

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Section: Primary Antibody Characterizationsupporting

confidence: 88%

Morphological and functional characterization of cholinergic interneurons in the dorsal horn of the mouse spinal cord

Mesnage

Gaillard

Godin

et al. 2011

J of Comparative Neurology

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“…Accordingly, several authors failed to detect internalization of the NK1 receptor after stimulation of A␤ fibers (Allen et al, 1999;Malcangio et al, 2000;Hughes et al, 2007). It has been proposed that substance P is upregulated in low-threshold myelinated primary afferents after certain types of nerve injury, and that release of substance P from these afferents contributes to the resulting allodynia (Noguchi et al, 1995;Devor, 2006; but see Ruscheweyh et al, 2007). This clearly cannot be the case in the present study.…”

Section: Discussioncontrasting

confidence: 69%

Glycine Inhibitory Dysfunction Induces a Selectively Dynamic, Morphine-Resistant, and Neurokinin 1 Receptor- Independent Mechanical Allodynia

Miraucourt¹,

Moisset²,

Dallel³

et al. 2009

J. Neurosci.

118

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Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. We recently provided a novel perspective on the mechanisms of this symptom by showing that a simple switch in trigeminal glycine synaptic inhibition can turn touch into pain by unmasking innocuous input to superficial dorsal horn nociceptive specific neurons through a local excitatory, NMDA-dependent neural circuit involving neurons expressing the gamma isoform of protein kinase C. Here, we further investigated the clinical relevance and processing of glycine disinhibition. First, we showed that glycine disinhibition with strychnine selectively induced dynamic but not static mechanical allodynia. The induced allodynia was resistant to morphine. Second, morphine did not prevent the activation of the neural circuit underlying allodynia as shown by study of Fos expression and extracellularsignal regulated kinase phosphorylation in dorsal horn neurons. Third, in contrast to intradermal capsaicin injections, light, dynamic mechanical stimuli applied under disinhibition did not produce neurokinin 1 (NK1) receptor internalization in dorsal horn neurons. Finally, light, dynamic mechanical stimuli applied under disinhibition induced Fos expression only in neurons that did not express NK1 receptor. To summarize, the selectivity and morphine resistance of the glycine-disinhibition paradigm adequately reflect the clinical characteristics of dynamic mechanical allodynia. The present findings thus reveal the involvement of a selective dorsal horn circuit in dynamic mechanical allodynia, which operates through superficial lamina nociceptive-specific neurons that do not bear NK1 receptor and provide an explanation for the differences in the pharmacological sensitivity of neuropathic pain symptoms.

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“…This result, plus the observation that GPR55 increases intracellular calcium, suggests that GPR55 activation enhances neuronal excitability. These findings, together with the preferential expression of GPR55 on large-diameter DRG neurons, which can be involved in nociception, particularly in neuropathic or inflammatory pain states (29)(30)(31), suggest that GPR55 may have a pronocioceptive role.…”

Section: Discussionmentioning

confidence: 92%

GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current

Lauckner

Jensen²,

Chen

et al. 2008

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

616

664

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The CB1 cannabinoid receptor mediates many of the psychoactive effects of ⌬ 9 THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB 1/CB2 receptors may contribute to the behavioral, vascular, and immunological actions of ⌬ 9 THC and endogenous cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled receptor, is a cannabinoid receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various cannabinoids (⌬ 9 THC, the anandamide analog methanandamide, and JWH015) increases intracellular calcium in these neurons. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve G q, G12, RhoA, actin, phospholipase C, and calcium release from IP 3R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a cannabinoid receptor with signaling distinct from CB 1 and CB2.orphan ͉ pain ͉ CB3 ͉ G protein-coupled receptor C annabis has been used and abused for its therapeutic and psychoactive properties for millennia. The effects of cannabinoid compounds are largely mediated by cannabinoid receptors. CB 1 , cloned in 1990 (1), is widely and highly expressed in the CNS, where it likely mediates the majority of the psychotropic and behavioral effects of cannabinoids. CB 2 is primarily expressed in peripheral tissues (2). Both CB 1 and CB 2 are 7-transmembrane G protein-coupled receptors that engage predominantly the G i/o family of G proteins. However, ample evidence suggests that additional receptors may contribute to the behavioral, vascular, and immunological actions of ⌬ 9 tetrahydrocannabinol (THC) and endogenous cannabinoids (3).It has been suggested that GPR55 is a novel cannabinoid receptor (reviewed in ref. 4). GPR55 is only 13.5% identical to CB 1 and 14.4% identical to CB 2 , and its mRNA is present in the brain and periphery (5-7). A recent study found that a variety of cannabinoid compounds stimulated GTP␥S binding in cells stably expressing GPR55 (6). Here, we report GPR55 activation by THC, JWH015, and anandamide increases intracellular calcium by activating signaling pathways quite distinct from those used by CB 1 and CB 2 . Results Activation of GPR55 by Cannabinoids Increases Intracellular Calcium.We first examined the signaling pathways activated by GPR55 in HEK293 cells transiently expressing human GPR55 (hGPR55). Perfusion with 5 M THC evoked a calcium increase (⌬[Ca 2ϩ ] i ) averaging Ϸ100 nM (n ϭ 7, Fig. 1 A and B). Perfusion with 3 M THC evoked a more modest increase (n ϭ 5, 50 nM; Fig. 1B). The agonist-induced calcium response was present in all cells tested, but because it varied in magnitude and time course, concurrent controls were always conducted. GPR55 was essential for the THC-evoked calcium rise because there was minimal calcium rise in nontransfected HEK293 cells exposed to 5 M THC (n ϭ 6, Fig. 1 A and B). A similar calcium increase was seen in CHO cells stably expressing hGPR55 (data not show...

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Modification of classical neurochemical markers in identified primary afferent neurons with Aβ‐, Aδ‐, and C‐fibers after chronic constriction injury in mice

Cited by 165 publications

References 52 publications

Morphological and functional characterization of cholinergic interneurons in the dorsal horn of the mouse spinal cord

Morphological and functional characterization of cholinergic interneurons in the dorsal horn of the mouse spinal cord

Glycine Inhibitory Dysfunction Induces a Selectively Dynamic, Morphine-Resistant, and Neurokinin 1 Receptor- Independent Mechanical Allodynia

GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current

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