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Possible role of protein kinase C in the sensitization of primate spinothalamic tract neurons.

ABSTRACT: The responsiveness of spinal cord nociceptive neurons to innocuous mechanical stimuli can be increased by the release of excitatory amino acids (EAAs) and peptides attributable to an injury-induced barrage of impulses. This sensitization of spinal dorsal horn neurons can also result from administration of phorbol ester by microdialysis, presumably by direct activation of protein kinase C (PKC). This study was designed to examine the effects of central sensitization of spinothalamic tract (STT) neurons produced by intradermal injection of capsaicin on the descending inhibition driven from the periaqueductal gray (PAG) and the possible role of PKC in this process in anesthetized monkeys. Sensitization of responses of STT cells to mechanical stimuli was induced by intradermal injection of capsaicin. PAG inhibition was significantly attenuated when sensitization of responses to mechanical stimuli occurred. However, perfusion of the spinal cord with NPC15437 (a selective PKC inhibitor) by microdialysis could prevent the sensitization of the responses to mechanical stimuli and the reduction in PAG inhibition of these responses induced by capsaicin injection. Results similar to those produced by capsaicin injection were observed when a PKC activator, phorbol ester (12-O-tetradecanoylphorbol-13-acetate), was infused within the dorsal horn by microdialysis. An inactive phorbol ester (4 alpha-phorbol 12,13-didecanoate) had no effect. These results provide evidence that the activation of PKC contributes to the development of central sensitization in dorsal horn neurons produced by chemical stimulation with capsaicin. Attenuation of the effectiveness of PAG inhibition takes place when the sensitization of dorsal horn cells develops, and PKC may play a significant role in this process.

SUBMITTER: Lin Q

PROVIDER: S-EPMC6579049 | biostudies-literature | 1996 May

REPOSITORIES: biostudies-literature

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Possible role of protein kinase C in the sensitization of primate spinothalamic tract neurons.

Lin Q Q Peng Y B YB Willis W D WD

The Journal of neuroscience : the official journal of the Society for Neuroscience 19960501 9

The responsiveness of spinal cord nociceptive neurons to innocuous mechanical stimuli can be increased by the release of excitatory amino acids (EAAs) and peptides attributable to an injury-induced barrage of impulses. This sensitization of spinal dorsal horn neurons can also result from administration of phorbol ester by microdialysis, presumably by direct activation of protein kinase C (PKC). This study was designed to examine the effects of central sensitization of spinothalamic tract (STT) n ...[more]

PMID: 8622132

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Project description:Objective: Revisiting the sharp/dull discrimination as clinical measure of spinothalamic tract function considering the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Three clinically relevant factors were evaluated as to their impact on reliability: (1) the localization of dermatomes in relation to the sensory level, (2) the examination tool, and (3) the threshold of correct answers for grading of a preserved sharp/dull discrimination. Design: Prospective monocentric psychometric study. Setting: Spinal Cord Injury Center, Heidelberg University Hospital, Germany. Participants: Convenient sample of 21 individuals with subacute spinal cord injury (age: 31-82 years) and 20 individuals without spinal cord injury (age: 24-63 years). Assessment: All participants underwent three assessments for sharp/dull discrimination, applying five commonly used examination tools in seven dermatomes, performed by three trained examiners under conditions in accordance with ISNCSCI. Main Outcome Measures: Assessment of interrater reliability by determining both the Fleiss kappa (κ) coefficient and the percentage agreement between raters. Data were dichotomized regarding the ISNCSCI threshold. Results: Interrater reliability in individuals with SCI was overall substantial (κ = 0.68; CI 0.679-0.681) and moderate (κ = 0.54; CI 0.539-0.543) in dermatomes below the sensory level. All applied tools led to at least moderate reliability below the sensory level (lowest κ = 0.44; CI 0.432-0.440), with the officially endorsed safety pin achieving the highest (substantial) reliability (κ = 0.64; CI 0.638-0.646). Percentage agreement differed between non-SCI (97.3%) and formally intact above level dermatomes in SCI (89.2%). Conclusions: Sharp/dull discrimination as a common clinical examination technique for spinothalamic tract function is a reliable assessment. Independent from the used examination tools, reliability was substantial, with the medium-sized safety pin delivering the most favorable results. Notwithstanding this, all other tools could be considered if a safety pin is not available. Regarding interrater reliability and guessing probability, a threshold of 80% correct responses for preserved sharp/dull discrimination appears to be most suitable, which is in line with current clinical approaches and ISNCSCI. The causal attribution of the identified differences in sharp/dull discrimination between clinically intact dermatomes of individuals with SCI and unaffected dermatomes of individuals without SCI requires future work. Clinical Trial Registration Number (German Clinical Trials Register): DRKS00015334 (https://www.drks.de).

Project description:ObjectiveIntestinal barrier function is vital for homeostasis. Conditions where the mucosal barrier is compromised lead to increased plasma content of lipopolysaccharide (LPS). LPS acts on Toll-like receptor 4 (TLR4) and initiates cellular inflammatory responses. TLR4 receptors have been identified on enteric neurons and LPS exposure causes neuronal loss, counteracted by vasoactive intestinal peptide (VIP), by unknown mechanisms. In addition AMP activated protein kinase (AMPK) stimulation causes loss of enteric neurons. This study investigated a possible role of AMPK activation in LPS-induced neuronal loss.DesignPrimary cultures of myenteric neurons isolated from rat small intestine were used. Cultures were treated with LPS (0.2-20 µg/mL) with and without TAK1-inhibitor (5Z)-7-Oxozeaenol (10-6 M) or AMPK inhibitor compound C (10-5 M). AMPK-induced neuronal loss was verified treating cultures with three different AMPK activators, AICAR (10-4-3×10-3 M), metformin (0.2-20 µg/mL) and A-769662 (10-5-3×10-4 M) with or without the presence of compound C (10-5 M). Upstream activation of AMPK-induced neuronal loss was tested by treating cultures with AICAR (10-3 M) in the presence of TAK1 inhibitor (5Z)-7-Oxozeaenol (10-6 M). Neuronal survival and relative numbers of neurons immunoreactive (IR) for VIP were evaluated using immunocytochemistry.ResultsLPS caused a concentration dependent loss of neurons. All AMPK activators induced loss of myenteric neurons in a concentration dependent manner. LPS-, AICAR- and metformin-,but not A-769662-, induced neuronal losses were inhibited by presence of compound C. LPS, AICAR or metformin exposure increased the relative number of VIP-IR neurons; co-treatment with (5Z)-7-Oxozeaenol or compound C reversed the relative increase in VIP-IR neurons induced by LPS. (5Z)-7-Oxozeaenol, compound C or A-769662 did not per se change neuronal survival or relative numbers of VIP-IR neurons.ConclusionAMPK activation mimics LPS-induced loss of cultured myenteric neurons and LPS-induced neuronal loss is counteracted by TAK1 and AMPK inhibition. This suggests enteric neuroimmune interactions involving AMPK regulation.

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Possible role of protein kinase C in the sensitization of primate spinothalamic tract neurons.

Publications

Possible role of protein kinase C in the sensitization of primate spinothalamic tract neurons.

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