DOCSLIB.ORG

Reduced Inflammatory Hyperalgesia with Preservation of Acute Thermal Nociception in Mice Lacking Cgmp-Dependent Protein Kinase I

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Reduced Inflammatory Hyperalgesia with Preservation of Acute Thermal Nociception in Mice Lacking Cgmp-Dependent Protein Kinase I Reduced inflammatory hyperalgesia with preservation of acute thermal nociception in mice lacking cGMP-dependent protein kinase I Irmgard Tegeder*†, Domenico Del Turco‡, Achim Schmidtko*, Matthias Sausbier§, Robert Feil¶, Franz Hofmann¶, Thomas Deller‡, Peter Ruth§, and Gerd Geisslinger* *pharmazentrum frankfurt and ‡Institut fu¨r Klinische Neuroanatomie, Klinikum der Johann Wolfgang Goethe-Universita¨t, 60590 Frankfurt am Main, Germany; §Pharmakologie und Toxikologie, Pharmazeutisches Institut, Universita¨t Tu¨ bingen, 72076 Tu¨bingen, Germany; and ¶Institut fu¨r Pharmakologie und Toxikologie der Technischen Universita¨t, 80802 Munich, Germany Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, and approved December 18, 2003 (received for review July 1, 2003) cGMP-dependent protein kinase I (PKG-I) has been suggested to tion on the PNAS web site.) Hence, the exact role of PKG-I in contribute to the facilitation of nociceptive transmission in the nociception remains elusive. spinal cord presumably by acting as a downstream target of nitric In the present study we used PKG-IϪ/Ϫ mice to clearly assess oxide. However, PKG-I activators caused conflicting effects on the role of PKG-I in nociception. Because these mice have a nociceptive behavior. In the present study we used PKG-I؊/؊ mice defective regulation of smooth muscle contraction with vascular to further assess the role of PKG-I in nociception. PKG-I deficiency and intestinal dysfunctions (17, 18), the overall constitution of Ϫ Ϫ was associated with reduced nociceptive behavior in the formalin homozygous PKG-I / mice deteriorates between 5 and 6 weeks assay and zymosan-induced paw inflammation. However, acute of age (17). We therefore used 3- to 4-week-old animals for thermal nociception in the hot-plate test was unaltered. After nociceptive experiments in the present study. spinal delivery of the PKG inhibitor, Rp-8-Br-cGMPS, nociceptive behavior of PKG-I؉/؉ mice was indistinguishable from that of Materials and Methods PKG-I؊/؊ mice. On the other hand, the PKG activator, 8-Br-cGMP Animals. The generation of the PKG-I null allele and genotyping (250 nmol intrathecally) caused mechanical allodynia only in PKG- was done as described (17). Mice were bred and maintained in -I؉/؉ mice, indicating that the presence of PKG-I was essential for the animal facility of the Institut fu¨r Pharmakologie und Tox this effect. Immunofluorescence studies of the spinal cord revealed ikologie der Technischen Universita¨t Munich. For nociceptive Ϫ/Ϫ ϩ/ϩ additional morphological differences. In the dorsal horn of 3- to testing PKG-I and litter-matched PKG-I mice were 4-week-old PKG-I؊/؊ mice laminae I–III were smaller and contained shipped to the Institut fu¨r Klinische Pharmakologie, Klinikum fewer neurons than controls. Furthermore, the density of sub- der Johann Wolfgang Goethe-Universita¨t Frankfurt. Experi- stance P-positive neurons and fibers was significantly reduced. The ments were performed the day after the arrival. Mice had free access to food and water before and during the experiments. The paucity of substance P in laminae I–III may contribute to the Ϯ ؊/؊ mean SD total body mass of wild-type and knockout mice was reduction of nociception in PKG-I mice and suggests a role of Ϯ Ϯ PKG-I in substance P synthesis. 16.2 2.7 g and 14.2 2.8 g, respectively (12.5% difference). The lean body mass differs by Ϸ8%. All experiments were approved by the local Ethics Committee for Animal Research spinal cord ͉ substance P ͉ nitric oxide ͉ pain and conformed to IASP ethical guidelines. he second messenger cGMP is formed by activation of Nociceptive Testing. Formalin assay. Fifteen microliters of a 5% Tsoluble and particulate guanylyl cyclases and has several formaldehyde solution was injected into the s.c. space at the targets, including cGMP-dependent protein kinase I (PKG-I) dorsal side of the right hind paw. The time spent licking the and PKG-II, of which PKG-I is expressed in the spinal cord (1, formalin-injected paw was recorded in 5-min intervals up to 45 2). Spinally delivered PKG inhibitors reduce formalin-induced min, starting right after formalin injection. The PKG-I inhibitor nociceptive behavior in rats (3, 4), suggesting that PKG-I plays Rp-8-Br-cGMPS (Biolog Life Sciences Institute, Bremen, Ger- an important role in spinal nociceptive processing. It has been many) was delivered onto the lumbar spinal cord by intrathecal speculated that PKG-I mediates hyperalgesic effects of nitric injection as has been described (19). The drug was dissolved in ϩ ϩ oxide (NO) (5). This idea is supported by the observation that artificial cerebrospinal fluid (141.7 mM Na ͞2.6 mM K ͞0.9 2ϩ͞ 2ϩ͞ Ϫ͞ Ϫ͞ PKG-I inhibition causes a reduction of thermal hyperalgesia mM Mg 1.3 mM Ca 122.7 mM Cl 21.0 mM HCO3 2.5 2Ϫ͞ induced by injection of the NO donor, NOC-12 (6). Endogenous mM HPO4 3.5 mM dextrose, bubbled with 5% CO2 in 95% O2 NO is produced by NO synthases, of which neuronal nitric oxide to adjust the pH to 7.2) and injected in a volume of 5 ␮l. The dose synthase (nNOS) is activated and up-regulated after N-methyl- (50 nmol) was 1͞10th of the dose previously found to reduce D-aspartate receptor stimulation (7–10). NO probably acts as a flinching behavior in rats (4, 15). Drug injection was performed retrograde messenger (11, 12) at nociceptive synapses, i.e., it is in short isoflurane anesthesia 10 min before the injection of released from the postsynaptic neuron, diffuses back to the formalin. presynaptic neuron, and stimulates guanylyl cyclases. The latter Mechanical hyperalgesia in zymosan-induced paw inflammation. Mice step links NO to cGMP production and PKG-I activation. were adapted to the test perspex chamber with a grid bottom for PHARMACOLOGY Because inhibition of NOS activity reduces nociception (13, 14), the release of NO is thought to contribute to the development This paper was submitted directly (Track II) to the PNAS office. of hyperexcitability of nociceptive neurons under certain cir- Abbreviation: MPWT, mechanical paw-withdrawal threshold; PKG, cGMP-dependent pro- cumstances. Under the premise that PKG-I is a mediator of NO tein kinase; LTP, long-term potentiation; nNOS, neuronal nitric oxide synthase. at nociceptive synapses, one would expect that PKG-I activation †To whom correspondence should be sent at the present address: NPRG, Department of also causes hyperalgesia. However, effects of the spinally deliv- Anesthesia, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, ered PKG activator 8-Br-cGMP have been conflicting (15, 16). Room 4309, Charlestown, MA 02129. E-mail: [email protected]. (See Supporting Text, which is published as supporting informa- © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0304076101 PNAS ͉ March 2, 2004 ͉ vol. 101 ͉ no. 9 ͉ 3253–3257 Downloaded by guest on September 25, 2021 at least 30 min before baseline testing. Fifteen microliters of a 10 tions, 1 ␮m) were obtained by using a Zeiss LSM 510 confocal mg͞ml zymosan (Sigma) suspension in PBS (0.1 M PBS, pH 7.4) laser-scanning microscope. was then injected into the plantar side of the right hind paw. Mechanical hyperalgesia was assessed before zymosan injection Image Analysis. For quantitative analysis of cell and fiber densi- and then hourly up to7hafterzymosan injection. The threshold ties, midlumbar spinal cord sections (L4͞5) from PKG-IϪ/Ϫ mice to mechanical nociceptive stimuli was assessed by means of a (n ϭ 3) and PKG-Iϩ/ϩ mice (n ϭ 3) were used. Quantification punctuated stimulation by using von Frey hairs of different was performed as described (21), with modifications. Sections strengths (0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, 2, 4, and 6 g; stained for substance P and NeuN and sections stained for nNOS Stoelting). They were placed perpendicularly onto the plantar and NeuN were analyzed (n ϭ 5 per animal per staining). surface of the right or left paw and bent slightly to apply Confocal images were captured by using identical settings for all punctuated pressure. The stimuli were applied at five repetitions sections. Images were analyzed with IMAGEJ 1.31 (http:͞͞ each and at increasing order until the paw was withdrawn and rsb.info.nih.gov͞ij). NeuN labeling of neurons was used to then at decreasing order until paw withdrawal stopped. This identify lamina I–III of the dorsal horn. Cell numbers, mean up-and-down testing was repeated after a short rest. The geo- pixel values, and areas of laminae I–III were determined and metric mean of uppermost (increasing testing) and lowest compared by using Student’s t test (SPSS 11.0). Values of P Ͻ 0.05 (decreasing testing) test results was taken as the mechanical were considered as statistically significant. paw-withdrawal threshold (MPWT). These data were log- transformed, and the percent decrease of the withdrawal thresh- Results old was then calculated in relation to the baseline withdrawal Formalin Assay. PKG-IϪ/Ϫ mice spent significantly less time threshold as: % decrease of MPWT ϭ MPWT࿝baseline Ϫ licking the formalin-injected hind paw than PKG-Iϩ/ϩ mice (Fig. MPWT࿝zymosan͞MPWT࿝baseline⅐100. 1). These differences occurred in the first and second phase of Mechanical allodynia induced by 8-Br-cGMP. After two baseline mea- the formalin assay. Injection of the PKG inhibitor Rp-8-Br- surements 250 nmol of 8-Br-cGMP was injected into the sub- cGMPS significantly reduced the licking behavior in PKG-Iϩ/ϩ arachnoid space of the lumbar spinal cord in 5 ␮l of artificial mice but had no effect in PKG-IϪ/Ϫ mice.
Load more

Recommended publications
  • Substance P: Transmitter O. Nociception (Minireview)
    ENDOCRINE REGULATIONS, Vol. 34,195201, 2000 195 SUBSTANCE P: TRANSMITTER O NOCICEPTION (MINIREVIEW) M. ZUBRZYCKA1, A. JANECKA2 1Department of Physiology and 2Department of General Chemistry, Institute of Physiology and Biochemistry, Medical University of Lodz, Lindleya 3, 90-131 Lodz, Poland E-mail: [email protected] Substance P plays the role of a neurotransmitter immunoreactive fibers has also been detected in lam- and neuromodulator in the central and peripheral ina V of the dorsal horn (LJUNGDAHL et al. 1978), lam- nervous system. The presence of substance P in de- ina X surrounding the central canal (LAMOTTE and myelinated sensory fibres, as well as in the small SHAPIRO 1991), the nucleus dorsalis, interomediolat- and medium-sized neurons of spinal dorsal horn sub- eral cell column, and the ventral horn (PIORO et stantia gelatinosa gives a structural basis for the al.1984). Electric stimulation of the dorsal root, or hypothesis that SP plays an important role of peripheral nerve endings, causes a substantial release a mediator in the processing of nociceptive informa- of SP within the substantia gelatinosa of spinal dor- tion. In this paper recent advances on the effect of sal horns (OTSUKA and KANISHI 1976). SP on conduction and modulation of nociceptive In the dorsal regions of the spinal dorsal horn, impulsation are reviewed. The studies concerning the besides SP also large quantities of gamma-aminobu- role of SP in the prevertebral ganglia and spinal dor- tyric acid (GABA) are present, but reduction of sal horns has been presented, including the distribu- GABA levels has no effect on the SP content, and tion of SP in the spinal cord, as well as its pre- and similarly, reduction of SP levels does not cause any postsynaptic actions on excitatory and inhibitory decrease of GABA concentration in this region of postsynaptic potentials (EPSP and IPSP) and the ef- the spinal cord (TAKAHASHI and OTSUKA 1975).
    [Show full text]
  • Recognition and Alleviation of Distress in Laboratory Animals
    http://www.nap.edu/catalog/11931.html We ship printed books within 1 business day; personal PDFs are available immediately. Recognition and Alleviation of Distress in Laboratory Animals Committee on Recognition and Alleviation of Distress in Laboratory Animals, National Research Council ISBN: 0-309-10818-7, 132 pages, 6 x 9, (2008) This PDF is available from the National Academies Press at: http://www.nap.edu/catalog/11931.html Visit the National Academies Press online, the authoritative source for all books from the National Academy of Sciences, the National Academy of Engineering, the Institute of Medicine, and the National Research Council: x Download hundreds of free books in PDF x Read thousands of books online for free x Explore our innovative research tools – try the “Research Dashboard” now! x Sign up to be notified when new books are published x Purchase printed books and selected PDF files Thank you for downloading this PDF. If you have comments, questions or just want more information about the books published by the National Academies Press, you may contact our customer service department toll- free at 888-624-8373, visit us online, or send an email to [email protected]. This book plus thousands more are available at http://www.nap.edu. Copyright © National Academy of Sciences. All rights reserved. Unless otherwise indicated, all materials in this PDF File are copyrighted by the National Academy of Sciences. Distribution, posting, or copying is strictly prohibited without written permission of the National Academies Press. Request reprint permission for this book. Recognition and Alleviation of Distress in Laboratory Animals http://www.nap.edu/catalog/11931.html Recognition and Alleviation of Distress in Laboratory Animals Committee on Recognition and Alleviation of Distress in Laboratory Animals Institute for Laboratory Animal Research Division on Earth and Life Studies THE NATIONAL ACADEMIES PRESS Washington, D.C.
    [Show full text]
  • Nociceptors – Characteristics?
    Nociceptors – characteristics? • ? • ? • ? • ? • ? • ? Nociceptors - true/false No – pain is an experience NonociceptornotNoNo – –all nociceptors– TRPV1 nociceptorsC fibers somata is areexpressed may alsoin have • Nociceptors are pain fibers typically associated with Typically yes, but therelowsensorynociceptorsinhave manyisor ahigh efferentsemantic gangliadifferent thresholds and functions mayproblemnot cells, all befor • All C fibers are nociceptors nociceptoractivationsmallnociceptorsincluding or large non-neuronalactivation are in Cdiameter fibers tissue • Nociceptors have small diameter somata • All nociceptors express TRPV1 channels • Nociceptors have high thresholds for response • Nociceptors have only afferent (sensory) functions • Nociceptors encode stimuli into the noxious range Nociceptors – outline Why are nociceptors important? What’s a nociceptor? Nociceptor properties – somata, axons, content, etc. Nociceptors in skin, muscle, joints & viscera Mechanically-insensitive nociceptors (sleeping or silent) Microneurography Heterogeneity Why are nociceptors important? • Pain relief when remove afferent drive • Afferent is more accessible • With peripherally restricted intervention, can avoid many of the most deleterious side effects Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input …. Price DD, Craggs JG, Zhou Q, Verne GN, et al. Neuroimage 47:995-1001, 2009 IBS IBS rectal rectal placebo lidocaine rectal lidocaine Time (min) Importantly, areas of somatic referral were
    [Show full text]
  • Monitoring the Nociception Level Intraoperatively - an Initial Experiences
    Research Article J Anest & Inten Care Med Volume 7 Issue 2 - July 2018 Copyright © All rights are reserved by Pether Jildenstål DOI: 10.19080/JAICM.2018.07.555709 Monitoring the Nociception Level Intraoperatively - An Initial Experiences Pether Jildenstål1,2*, Katarina Hallén2, Katarina Almskog3, Johan Sand3 and Margareta Warren Stomberg1 1Institute of Health and Care Sciences, University of Gothenburg, Sweden 2Department of Anesthesiology, Surgery and Intensive Care, Sahlgrenska University Hospital, Sweden 3Department of Anesthesiology and Intensive care, Queen Silvia Children’s Hospital, Sweden Submission: July 5, 2018; Published: July 25, 2018 *Corresponding author: Pether Jildenstål, Institute of Health and Care Sciences, University of Gothenburg, Sweden, Email: Abstract Background: when vasopressors are used as well. There is an increasing interest during general anesthesia to understand how optimal anesthesia changes by Estimating pain stimuli in the anesthetized patient can be difficult when based solely upon physiological parameters, especially its exact use in routine clinical practice is still not well proven. The aim of this study was to identify relationships between PMD 200 monitoring, Nociceptionthe level of noxious Level (NOL-index) stimulation. and Objectively, monitored noxious known stimulation physiological measurement signs as well monitoring as outcomes techniques during general are gaining anesthesia. interest. Although currently, Method: during the intraoperativeEight patients period. between the ages of 43 and 83 years old and scheduled for major head and neck surgery under general anesthesia were observed in this study. NoL index sensor was placed on one of the patient’s fingers before anesthesia was induced, and values were extracted Results: of the bladder, and with surgical skin incision.
    [Show full text]
  • Ion Channels of Nociception
    International Journal of Molecular Sciences Editorial Ion Channels of Nociception Rashid Giniatullin A.I. Virtanen Institute, University of Eastern Finland, 70211 Kuopio, Finland; Rashid.Giniatullin@uef.fi; Tel.: +358-403553665 Received: 13 May 2020; Accepted: 15 May 2020; Published: 18 May 2020 Abstract: The special issue “Ion Channels of Nociception” contains 13 articles published by 73 authors from different countries united by the main focusing on the peripheral mechanisms of pain. The content covers the mechanisms of neuropathic, inflammatory, and dental pain as well as pain in migraine and diabetes, nociceptive roles of P2X3, ASIC, Piezo and TRP channels, pain control through GPCRs and pharmacological agents and non-pharmacological treatment with electroacupuncture. Keywords: pain; nociception; sensory neurons; ion channels; P2X3; TRPV1; TRPA1; ASIC; Piezo channels; migraine; tooth pain Sensation of pain is one of the fundamental attributes of most species, including humans. Physiological (acute) pain protects our physical and mental health from harmful stimuli, whereas chronic and pathological pain are debilitating and contribute to the disease state. Despite active studies for decades, molecular mechanisms of pain—especially of pathological pain—remain largely unaddressed, as evidenced by the growing number of patients with chronic forms of pain. There are, however, some very promising advances emerging. A new field of pain treatment via neuromodulation is quickly growing, as well as novel mechanistic explanations unleashing the efficiency of traditional techniques of Chinese medicine. New molecular actors with important roles in pain mechanisms are being characterized, such as the mechanosensitive Piezo ion channels [1]. Pain signals are detected by specialized sensory neurons, emitting nerve impulses encoding pain in response to noxious stimuli.
    [Show full text]
  • Headache and Musculoskeletal Pain in School Children Are Associated with Uncorrected Vision Problems and Need for Glasses
    www.nature.com/scientificreports OPEN Headache and musculoskeletal pain in school children are associated with uncorrected vision problems and need for glasses: a case–control study Hanne‑Mari Schiøtz Thorud*, Rakel Aurjord & Helle K. Falkenberg Musculoskeletal pain and headache are leading causes of years lived with disability, and an escalating problem in school children. Children spend increasingly more time reading and using digital screens, and increased near tasks intensify the workload on the precise coordination of the visual and head‑ stabilizing systems. Even minor vision problems can provoke headache and neck‑ and shoulder (pericranial) pain. This study investigated the association between headaches, pericranial tenderness, vision problems, and the need for glasses in children. An eye and physical examination was performed in twenty 10–15 year old children presenting to the school health nurse with headache and pericranial pain (pain group), and twenty age‑and‑gender matched classmates (control group). The results showed that twice as many children in the pain group had uncorrected vision and needed glasses. Most children were hyperopic, and glasses were recommended mainly for near work. Headache and pericranial tenderness were signifcantly correlated to reduced binocular vision, reduced distance vision, and the need for new glasses. That uncorrected vision problems are related to upper body musculoskeletal symptoms and headache, indicate that all children with these symptoms should have a full eye examination to promote health
    [Show full text]
  • A Surgical Opinion on Hyperalgesia/Nociception
    Send Orders of Reprints at [email protected] Current Immunology Reviews, 2012, 8, 275-286 275 A Surgical Opinion on Hyperalgesia/Nociception, Inflammatory/Neurogenic Pain and Anti-inflammatory Responses and Drug Interventions Revisited: Current Breakthroughs and Views John J. Haddad* Cellular and Molecular Physiology and Immunology Signaling Research Group, Biomedical Laboratory and Clinical Sciences Division, Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon Abstract: All sensory modalities are essentially important, but pain serves a protective function and is indispensable for survival, and, technically, pain is considered one of the most common symptoms of injuries and related diseases. Inflammatory cells and inflammatory mediators are crucially involved in the propensity, genesis, persistence and severity of pain, commonly known as nociception or hyperalgesia, following trauma, infection, or nerve injury. When it pins down to the essential understanding of pain/hyperalgesia pathways and their intricate interactions with myriad probabilities of milieu of inflammatory cytokines and related molecules, the amicable concept of specificity and complexity remains a major dilemma. Various hyperalgesic models have been established to investigate this intricate relationship between pain perception and inflammatory responses. Illness-induced hyperalgesia, for instance, is one of the most common aspects of pain related-inflammation and therapeutic approach to this pain should aim at interfering with various mediators of the inflammatory reactions, including neuropeptides, eicosanoids and cytokines. In this surgical synopsis, a trajectory of neurochemical events and cascades are delineated and unraveled in terms of the connection that has ostensibly evolved for hyperalgesia-inflammatory responses. The unprecedented intricacy of pain-inflammatory relationship and putative pathways bears surmountable clinical and physiological relevance.
    [Show full text]
  • NOL™ Technology, the PMD-200™ Is a Non-Invasive and Continuous Pain Monitoring Device
    ™ NOL (Nociception Level) Technology Intraoperative Pain Monitoring for Optimizing Analgesia Accurate & Objective Optimization & Faster Response Time Standardization assessment of Personalization through earlier detection among physicians nociception of analgesic treatment of nociception THE CHALLENGE Assessing Intraoperative Pain Reliably Treating pain is at the heart of medicine. It is an essential role of every clinician, since unmanaged pain can delay recovery, increase morbidity and mortality, and overburden healthcare resources. Nociception - Pain in Anaesthetized Patients During general anaesthesia, a patient’s body reacts to painful stimuli – although it is not consciously recognized. This intraoperative pain can stress the body1-4 and worsen pain after surgery4,5. As the patient can’t communicate – it is hard for clinicians to evaluate. Missing a Piece? While Hypnosis and Immobility are continuously and specifically monitored, analgesia is assessed indirectly ANALGESIA through changes in hemodynamic and clinical parameters (Heart Rate, Blood Pressure, Sweating, Tearing, etc.). These parameters are not specific to nociception, and may change in response to other causes as well. Consequently, patients may be given insufficient analgesia, which may promote postoperative pain4,5, or excessive analgesia, which may cause respiratory HYPNOSIS IMMOBILITY complications1,6, nausea and vomiting7, hyperalgesia8,9, and other complications1-11. Getting the right dose of anti-nociceptive medications matters. Too little, and patients wake up in pain. Too much, and patients are at risk of drug-related complications. Dr. Daniel Sessler, Head of the Department of Outcomes Research, Cleveland Clinic, Ohio, USA. A member of Medasense’s advisory board. 2 Each Year, Worldwide: 3.3 extra days of hospitalization 27% extra cost per patient UP TO of surgical50% patients suffer of surgical 12% patients suffer from moderate to severe from adverse events due 12-13 Increase in post-operative pain .
    [Show full text]
  • Spinal Neurons That Possess the Substance P Receptor Are Required for the Development of Central Sensitization
    The Journal of Neuroscience, October 15, 2002, 22(20):9086–9098 Spinal Neurons that Possess the Substance P Receptor Are Required for the Development of Central Sensitization Sergey G. Khasabov,1,2 Scott D. Rogers,1 Joseph R. Ghilardi,1 Christopher M. Peters,1 Patrick W. Mantyh,1,3,4 and Donald A. Simone2,3,4 Departments of 1Preventive Sciences, 2Oral Science, 3Psychiatry, and 4Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455 In previous studies, we have shown that loss of spinal neurons sponses to 10 ␮g of capsaicin were ϳ65% lower in animals that possess the substance P receptor (SPR) attenuated pain pretreated with SP-SAP compared with controls. Additionally, and hyperalgesia produced by capsaicin, inflammation, and sensitization to mechanical and heat stimuli that normally fol- nerve injury. To determine the role of SPR-expressing neurons lows capsaicin was rarely observed. Importantly, responses to in modulating pain and hyperalgesia, responses of superficial mechanical and heat stimuli in the absence of capsaicin were and deep lumbar spinal dorsal horn neurons evoked by me- not altered after SP-SAP treatment. In addition, nociceptive chanical and heat stimuli and by capsaicin were made after neurons did not exhibit windup in the SP-SAP-treated group. ablation of SPR-expressing neurons using the selective cyto- These results demonstrate that SPR-expressing neurons lo- toxin conjugate substance P-saporin (SP-SAP). Morphological cated in the dorsal horn are a pivotal component of the spinal analysis and electrophysiological recordings were made after circuits involved in triggering central sensitization and hyperal- intrathecal infusion of vehicle, saporin alone, or SP-SAP.
    [Show full text]
  • NOCICEPTORS and the PERCEPTION of PAIN Alan Fein
    NOCICEPTORS AND THE PERCEPTION OF PAIN Alan Fein, Ph.D. Revised May 2014 NOCICEPTORS AND THE PERCEPTION OF PAIN Alan Fein, Ph.D. Professor of Cell Biology University of Connecticut Health Center 263 Farmington Ave. Farmington, CT 06030-3505 Email: [email protected] Telephone: 860-679-2263 Fax: 860-679-1269 Revised May 2014 i NOCICEPTORS AND THE PERCEPTION OF PAIN CONTENTS Chapter 1: INTRODUCTION CLASSIFICATION OF NOCICEPTORS BY THE CONDUCTION VELOCITY OF THEIR AXONS CLASSIFICATION OF NOCICEPTORS BY THE NOXIOUS STIMULUS HYPERSENSITIVITY: HYPERALGESIA AND ALLODYNIA Chapter 2: IONIC PERMEABILITY AND SENSORY TRANSDUCTION ION CHANNELS SENSORY STIMULI Chapter 3: THERMAL RECEPTORS AND MECHANICAL RECEPTORS MAMMALIAN TRP CHANNELS CHEMESTHESIS MEDIATORS OF NOXIOUS HEAT TRPV1 TRPV1 AS A THERAPEUTIC TARGET TRPV2 TRPV3 TRPV4 TRPM3 ANO1 ii TRPA1 TRPM8 MECHANICAL NOCICEPTORS Chapter 4: CHEMICAL MEDIATORS OF PAIN AND THEIR RECEPTORS 34 SEROTONIN BRADYKININ PHOSPHOLIPASE-C AND PHOSPHOLIPASE-A2 PHOSPHOLIPASE-C PHOSPHOLIPASE-A2 12-LIPOXYGENASE (LOX) PATHWAY CYCLOOXYGENASE (COX) PATHWAY ATP P2X RECEPTORS VISCERAL PAIN P2Y RECEPTORS PROTEINASE-ACTIVATED RECEPTORS NEUROGENIC INFLAMMATION LOW pH LYSOPHOSPHATIDIC ACID Epac (EXCHANGE PROTEIN DIRECTLY ACTIVATED BY cAMP) NERVE GROWTH FACTOR Chapter 5: Na+, K+, Ca++ and HCN CHANNELS iii + Na CHANNELS Nav1.7 Nav1.8 Nav 1.9 Nav 1.3 Nav 1.1 and Nav 1.6 + K CHANNELS + ATP-SENSITIVE K CHANNELS GIRK CHANNELS K2P CHANNELS KNa CHANNELS + OUTWARD K CHANNELS ++ Ca CHANNELS HCN CHANNELS Chapter 6: NEUROPATHIC PAIN ANIMAL
    [Show full text]
  • Nociceptioncomplex BIT
    NociceptionCOMPLEX BIT Nociceptors are high threshold free nerve endings (A and There can be nociception without the conscious experience of C fibres). They respond to noxious stimulus and transduce/ pain such as getting a scratch or bruise without being aware encode this stimulus and then project an afferent signal to the of it and also we can have pain without bodies parts to contain spinal cord where they synapse with second order neurons in nociceptors with phenomenon such as phantom limb pain. the dorsal horn. Many second order neurons have ascending axons to supra spinal sites within the brain stem and brain. This These signals can be turned up or down by the many stages process is called nociception. of processing that MAY eventually end up as the conscious experience of pain based on the many affective/behavioral Most nociceptors are polymodal meaning they respond aspects that make up humans. to noxious stimulus arising from mechanical, thermal and chemical stimulus. The mechanical sensitivity of many nocicpetors increases, meaning the mechanical threshold for activation drops, an example being after the chemical irritation that can occur during inflammation. The thresholds required to activate nociceptors are variable in different tissues meaning they may have different responses. Nociception is no longer seen as a simple process whereby a “pain signal” is transmitted and faithfully reproduced as the sensation of pain. A well used phrase is “nociception is neither sufficient or necessary for pain” and is only one part of the multi dimensional nature of pain. Discover more at cor-kinetic.com Nociception SIMPLE SIDE Nociceptors have been described simply as “danger sensors” On its own this is pretty insignificant.
    [Show full text]
  • Does Nociception Monitor-Guided
    Journal of Clinical Monitoring and Computing (2020) 34:629–641 https://doi.org/10.1007/s10877-019-00362-4 REVIEW PAPER Does nociception monitor‑guided anesthesia afect opioid consumption? A systematic review of randomized controlled trials Fleur S. Meijer1 · Marieke Niesters1 · Monique van Velzen1 · Chris H. Martini1 · Erik Olofsen1 · Ruth Edry2 · Daniel I. Sessler3 · Eveline L. A. van Dorp1 · Albert Dahan1 · Martijn Boon1 Received: 25 February 2019 / Accepted: 16 July 2019 / Published online: 20 July 2019 © The Author(s) 2019 Abstract Monitors that estimate nociception during anesthesia may be used to guide opioid and other analgesics administration to optimize anesthesia care and possibly outcome. We reviewed the literature to evaluate current evidence of the efect of nociception-guided management over standard anesthesia practice during surgery. A systematic review of the literature on the efect of nociception monitoring on anesthesia practice was conducted. Reports were eligible if they compared nociception-guided anesthesia to standard practice during surgery. Primary endpoint of this review is intraoperative opioid consumption. Secondary endpoints included hemodynamic control, postoperative pain and pain treatment. We identifed 12 randomized controlled trials that compared one of fve diferent nociception monitoring techniques to standard anesthesia care. Most studies were single center studies of small sample size. Six studies reported intraoperative opioid consumption as primary outcome. There was considerable variability with respect to surgical procedure and anesthesia technique. For nociception monitors that were investigated by more than one study, analysis of the pooled data was performed. The surgi- cal plethysmographic index was the only monitor for which an intra operative opioid sparing efect was found.
    [Show full text]