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Sensory Nerves pp 495–518Cite as

Opioids and Sensory Nerves

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 194))

Abstract

This chapter reviews the expression and regulation of opioid receptors in sensory neurons and the interactions of these receptors with endogenous and exogenous opioid ligands. Inflammation of peripheral tissues leads to increased synthesis and axonal transport of opioid receptors in dorsal root ganglion neurons. This results in opioid receptor upregulation and enhanced G protein coupling at peripheral sensory nerve terminals. These events are dependent on neuronal electrical activity, and on production of proinflammatory cytokines and nerve growth factor within the inflamed tissue. Together with the disruption of the perineurial barrier, these factors lead to an enhanced analgesic efficacy of peripherally active opioids. The major local source of endogenous opioid ligands (e.g. β-endorphin) is leukocytes. These cells contain and upregulate signal-sequence-encoding messenger RNA of the β-endorphin precursor proopiomelanocortin and the entire enzymatic machinery necessary for its processing into the functionally active peptide. Opioid-containing immune cells extravasate using adhesion molecules and chemokines to accumulate in inflamed tissues. Upon stressful stimuli or in response to releasing agents such as corticotropin-releasing factor, cytokines, chemokines, and catecholamines, leukocytes secrete opioids. Depending on the cell type, this release is contingent on extracellular Ca2+ or on inositol triphosphate receptor triggered release of Ca2+ from endoplasmic reticulum. Once secreted, opioid peptides activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of proinflammatory neuropeptides. These effects occur without central untoward side effects such as depression of breathing, clouding of consciousness, or addiction. Future aims include the development of peripherally restricted opioid agonists, selective targeting of opioid-containing leukocytes to sites of painful injury, and the augmentation of peripheral opioid peptide and receptor synthesis.

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References

  • Akins PT, McCleskey EW (1993) Characterization of potassium currents in adult rat sensory neurons and modulation by opioids and cyclic AMP. Neuroscience 56:759–769

    PubMed  CAS  Google Scholar 

  • American Society of Anesthesiologists Task Force on Acute Pain Management (2004) Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 100:1573–1581

    Google Scholar 

  • Antonijevic I, Mousa SA, Schäfer M, Stein C (1995) Perineurial defect and peripheral opioid analgesia in inflammation. J Neurosci 15:165–172

    PubMed  CAS  Google Scholar 

  • Baamonde A, Lastra A, Juarez L, Garcia V, Hidalgo A, Menendez L (2005) Effects of the local administration of selective mu-, delta- and kappa-opioid receptor agonists on osteosarcoma-induced hyperalgesia. Naunyn Schmiedebergs Arch Pharmacol 372:213–219

    PubMed  CAS  Google Scholar 

  • Baamonde A, Lastra A, Juarez L, Garcia-Suarez O, Meana A, Hidalgo A, Menendez L (2006) Endogenous beta-endorphin induces thermal analgesia at the initial stages of a murine osteosarcoma. Peptides 27:2778–2785

    PubMed  CAS  Google Scholar 

  • Ballet S, Conrath M, Fischer J, Kaneko T, Hamon M, Cesselin F (2003) Expression and G-protein coupling of mu-opioid receptors in the spinal cord and dorsal root ganglia of polyarthritic rats. Neuropeptides 37:211–219

    PubMed  CAS  Google Scholar 

  • Bartho L, Stein C, Herz A (1990) Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation. Naunyn Schmiedebergs Arch Pharmacol 342:666–670

    PubMed  CAS  Google Scholar 

  • Beland B, Fitzgerald M (2001) Mu- and delta-opioid receptors are downregulated in the largest diameter primary sensory neurons during postnatal development in rats. Pain 90: 143–150

    Google Scholar 

  • Berg KA, Zardeneta G, Hargreaves KM, Clarke WP, Milam SB (2007a) Integrins regulate opioid receptor signaling in trigeminal ganglion neurons. Neuroscience 144:889–897

    PubMed  CAS  Google Scholar 

  • Berg KA, Patwardhan AM, Sanchez TA, Silva YM, Hargreaves KM, Clarke WP (2007b) Rapid modulation of mu-opioid receptor signaling in primary sensory neurons. J Pharmacol Exp Ther 321:839–847

    PubMed  CAS  Google Scholar 

  • Bergström J, Ahmed M, Li J, Ahmad T, Kreicbergs A, Spetea M (2006) Opioid peptides and receptors in joint tissues: study in the rat. J Orthop Res 24:1193–1199

    PubMed  Google Scholar 

  • Beutler AS, Banck MS, Walsh CE, Milligan ED (2005) Intrathecal gene transfer by adeno-associated virus for pain. Curr Opin Mol Ther 7:431–439

    PubMed  CAS  Google Scholar 

  • Bileviciute-Ljungar I, Spetea M, Guo Y, Schutz J, Windisch P, Schmidhammer H (2006) Peripherally mediated antinociception of the mu-opioid receptor agonist 2-[(4,5α-epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic acid (HS-731) after subcutaneous and oral administration in rats with carrageenan-induced hindpaw inflammation. J Pharmacol Exp Ther 317:220–227

    PubMed  CAS  Google Scholar 

  • Binder W, Mousa SA, Sitte N, Kaiser M, Stein C, Schäfer M (2004) Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue. Eur J Neurosci 20:92–100

    PubMed  Google Scholar 

  • Brack A, Rittner HL, Machelska H, Beschmann K, Sitte N, Schäfer M, Stein C (2004a) Mobilization of opioid-containing polymorphonuclear cells by hematopoietic growth factors and influence on inflammatory pain. Anesthesiology 100:149–157

    PubMed  CAS  Google Scholar 

  • Brack A, Rittner HL, Machelska H, Leder K, Mousa SA, Schafer M, Stein C (2004b) Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells. Pain 112:229–238

    PubMed  CAS  Google Scholar 

  • Brack A, Labuz D, Schiltz A, Rittner HL, Machelska H, Schafer M, Reszka R, Stein C (2004c) Tissue monocytes/macrophages in inflammation: hyperalgesia versus opioid-mediated peripheral antinociception. Anesthesiology 101:204–211

    PubMed  CAS  Google Scholar 

  • Brower V (2000) New paths to pain relief. Nat Biotechnol 18:387–391

    PubMed  CAS  Google Scholar 

  • Buzas B, Cox BM (1997) Quantitative analysis of mu- and delta-opioid receptor gene expression in rat brain and peripheral ganglia using competitive polymerase chain reaction. Neuroscience 76:479–489

    PubMed  CAS  Google Scholar 

  • Cabot PJ, Carter L, Gaiddon C, Zhang Q, Schäfer M, Loeffler JP, Stein C (1997) Immune cell-derived β-endorphin: production, release and control of inflammatory pain in rats. J Clin Invest 100:142–148

    PubMed  CAS  Google Scholar 

  • Cabot PJ, Carter L, Schäfer M, Stein C (2001) Methionine-enkephalin- and dynorphin A-release from immune cells and control of inflammatory pain. Pain 93:207–212

    PubMed  CAS  Google Scholar 

  • Calza L, Pozza M, Zanni M, Manzini CU, Manzini E, Hokfelt T (1998) Peptide plasticity in primary sensory neurons and spinal cord during adjuvant-induced arthritis in the rat: an immunocytochemical and in situ hybridization study. Neuroscience 82:575–589

    PubMed  CAS  Google Scholar 

  • Carlton SM, Coggeshall RE (1997) Immunohistochemical localization of enkephalin in peripheral sensory axons in the rat. Neurosci Lett 221:121–124

    PubMed  CAS  Google Scholar 

  • Chadzinska M, Starowicz K, Scislowska-Czarnecka A, Bilecki W, Pierzchala-Koziec K, Przewlocki R, Przewlocka B, Plytycz B (2005) Morphine-induced changes in the activity of proopiomelanocortin and prodynorphin systems in zymosan-induced peritonitis in mice. Immunol Lett 101:185–192

    PubMed  CAS  Google Scholar 

  • Chakass D, Philippe D, Erdual E, Dharancy S, Malapel M, Dubuquoy C, Thuru X, Gay J, Gaveriaux-Ruff C, Dubus P, Mathurin P, Kieffer BL, Desreumaux P, Chamaillard M (2007) Mu-opioid receptor activation prevents acute hepatic inflammation and cell death. Gut 56:974–981

    PubMed  CAS  Google Scholar 

  • Chen JJ, Dymshitz J, Vasko MR (1997) Regulation of opioid receptors in rat sensory neurons in culture. Mol Pharmacol 51:666–673

    PubMed  CAS  Google Scholar 

  • Chen CL, Broom DC, Liu Y, de Nooij JC, Li Z, Cen C, Samad OA, Jessell TM, Woolf CJ, Ma Q (2006) Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron 49:365–377

    PubMed  CAS  Google Scholar 

  • Coggeshall RE, Zhou S, Carlton SM (1997) Opiate receptors on peripheral sensory axons. Brain Res 764:126–132

    PubMed  CAS  Google Scholar 

  • Craft RM, Henley SR, Haaseth RC, Hruby VJ, Porreca F (1995) Opioid antinociception in a rat model of visceral pain: systemic versus local drug administration. J Pharmacol Exp Ther 275:1535–1542

    PubMed  CAS  Google Scholar 

  • Crowe R, Parkhouse N, McGrouther D, Burnstock G (1994) Neuropeptide-containing nerves in painful hypertrophic human scar tissue. Br J Dermatol 130:444–452

    PubMed  CAS  Google Scholar 

  • Cunha FQ, Ferreira SH (2003) Peripheral hyperalgesic cytokines. Adv Exp Med Biol 521:22–39

    PubMed  CAS  Google Scholar 

  • Czlonkowski A, Stein C, Herz A (1993) Peripheral mechanisms of opioid antinociception in inflammation: involvement of cytokines. Eur J Pharmacol 242:229–235

    PubMed  CAS  Google Scholar 

  • Dahan A, van Dorp E, Smith T, Yassen A (2008) Morphine-6-glucuronide (M6G) for postoperative pain relief. Eur J Pain 12:403–411

    PubMed  CAS  Google Scholar 

  • DeHaven-Hudkins DL, Dolle RE (2004) Peripherally restricted opioid agonists as novel analgesic agents. Curr Pharm Des 10:743–757

    PubMed  CAS  Google Scholar 

  • Eisenach JC, Carpenter R, Curry R (2003) Analgesia from a peripherally active κ-opioid receptor agonist in patients with chronic pancreatitis. Pain 101:89–95

    PubMed  CAS  Google Scholar 

  • Eisinger DA, Ammer H, Schulz R (2002) Chronic morphine treatment inhibits opioid receptor desensitization and internalization. J Neurosci 22:10192–10200

    PubMed  CAS  Google Scholar 

  • Endres-Becker J, Heppenstall PA, Mousa SA, Labuz D, Oksche A, Schäfer M, Stein C, Zöllner C (2007) Mu-opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain. Mol Pharmacol 71:12–18

    PubMed  CAS  Google Scholar 

  • Evans CJ, Keith DE Jr, Morrison H, Magendzo K, Edwards RH (1992) Cloning of a delta-opioid receptor by functional expression. Science 258:1952–1955

    PubMed  CAS  Google Scholar 

  • Fichna J, Janecka A, Costentin J, Do Rego JC (2007) The endomorphin system and its evolving neurophysiological role. Pharmacol Rev 59:88–123

    PubMed  CAS  Google Scholar 

  • Fürst S, Riba P, Friedmann T, Timar J, Al-Khrasani M, Obara I, Makuch W, Spetea M, Schutz J, Przewlocki R, Przewlocka B, Schmidhammer H (2005) Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. J Pharmacol Exp Ther 312:609–618

    PubMed  Google Scholar 

  • Gendron L, Lucido AL, Mennicken F, O'Donnell D, Vincent JP, Stroh T, Beaudet A (2006) Morphine and pain-related stimuli enhance cell surface availability of somatic delta-opioid receptors in rat dorsal root ganglia. J Neurosci 26:953–962

    PubMed  CAS  Google Scholar 

  • Gibbins IL, Furness JB, Costa M (1987) Pathway-specific patterns of the co-existence of substance P, calcitonin gene-related peptide, cholecystokinin and dynorphin in neurons of the dorsal root ganglia of the guinea pig. Cell Tissue Res 248:417–437

    PubMed  CAS  Google Scholar 

  • Gold MS, Levine JD (1996) DAMGO inhibits prostaglandin E2-induced potentiation of a TTX-resistant Na+ current in rat sensory neurons in vitro. Neurosci Lett 212:83–86

    PubMed  CAS  Google Scholar 

  • Hanna MH, Elliott KM, Fung M (2005) Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery. Anesthesiology 102:815–821

    PubMed  CAS  Google Scholar 

  • Hanninen A, Salmi M, Simell O, Andrew D, Jalkanen S (1996) Recirculation and homing of lymphocyte subsets: dual homing specificity of beta 7-integrin(high)-lymphocytes in nonobese diabetic mice. Blood 88:934–944

    PubMed  CAS  Google Scholar 

  • Hargreaves KM, Dubner R, Costello AH (1989) Corticotropin releasing factor (CRF) has a peripheral site of action for antinociception. Eur J Pharmacol 170:275–279

    PubMed  CAS  Google Scholar 

  • Hassan AHS, Ableitner A, Stein C, Herz A (1993) Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 55:185–195

    PubMed  CAS  Google Scholar 

  • Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, Catterall WA (1996) Modulation of Ca2+ channels by G-protein beta gamma subunits. Nature 380:258–262

    PubMed  CAS  Google Scholar 

  • Hermanussen S, Do M, Cabot PJ (2004) Reduction of beta-endorphin-containing immune cells in inflamed paw tissue corresponds with a reduction in immune-derived antinociception: reversible by donor activated lymphocytes. Anesth Analg 98:723–729

    PubMed  CAS  Google Scholar 

  • Heurich M, Mousa SA, Lenzner M, Morciniec P, Kopf A, Welte M, Stein C (2007) Influence of pain treatment by epidural fentanyl and bupivacaine on homing of opioid-containing leukocytes to surgical wounds. Brain Behav Immun 21:544–552

    PubMed  CAS  Google Scholar 

  • Hook S, Camberis M, Prout M, Konig M, Zimmer A, Van Heeke G, Le Gros G (1999) Preproenkephalin is a Th2 cytokine but is not required for Th2 differentiation in vitro. Immunol Cell Biol 77:385–390

    PubMed  CAS  Google Scholar 

  • Hua S, Hermanussen S, Tang L, Monteith GR, Cabot PJ (2006) The neural cell adhesion molecule antibody blocks cold water swim stress-induced analgesia and cell adhesion between lymphocytes and cultured dorsal root ganglion neurons. Anesth Analg 103:1558–1564

    PubMed  CAS  Google Scholar 

  • Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Makriyannis A, Vanderah TW, Mata HP, Malan TP Jr (2005) CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA 102:3093–3098

    PubMed  CAS  Google Scholar 

  • Ingram SL, Williams JT (1994) Opioid inhibition of Ih via adenylyl cyclase. Neuron 13:179–186

    PubMed  CAS  Google Scholar 

  • Jaber L, Swaim WD, Dionne RA (2003) Immunohistochemical localization of mu-opioid receptors in human dental pulp. J Endod 29:108–110

    PubMed  CAS  Google Scholar 

  • Jeanjean AP, Moussaoui SM, Maloteaux J-M, Laduron PM (1995) Interleukin-1β induces long-term increase of axonally transported opiate receptors and substance P. Neuroscience 68:151–157

    PubMed  CAS  Google Scholar 

  • Ji R-R, Zhang Q, Law P-Y, Low HH, Elde R, Hökfelt T (1995) Expression of μ-, δ-, and κ-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci 15:8156–8166

    PubMed  CAS  Google Scholar 

  • Kabli N, Cahill CM (2007) Anti-allodynic effects of peripheral delta-opioid receptors in neuropathic pain. Pain 127:84–93

    PubMed  CAS  Google Scholar 

  • Kalso E, Smith L, McQuay HJ, Moore RA (2002) No pain, no gain: clinical excellence and scientific rigour – lessons learned from IA morphine. Pain 98:269–275

    PubMed  CAS  Google Scholar 

  • Kavelaars A, Ballieux RE, Heijnen CJ (1990) In vitro beta-adrenergic stimulation of lymphocytes induces the release of immunoreactive beta-endorphin. Endocrinology 126:3028–3032

    PubMed  CAS  Google Scholar 

  • Khodorova A, Navarro B, Jouaville LS, Murphy JE, Rice FL, Mazurkiewicz JE, Long-Woodward D, Stoffel M, Strichartz GR, Yukhananov R, Davar G (2003) Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med 9:1055–1061

    PubMed  CAS  Google Scholar 

  • Kieffer BL, Gaveriaux-Ruff C (2002) Exploring the opioid system by gene knockout. Prog Neurobiol 66:285–306

    PubMed  CAS  Google Scholar 

  • Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG (1992) The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA 89:12048–12052

    PubMed  CAS  Google Scholar 

  • Koch T, Widera A, Bartzsch K, Schulz S, Brandenburg LO, Wundrack N, Beyer A, Grecksch G, Hollt V (2005) Receptor endocytosis counteracts the development of opioid tolerance. Mol Pharmacol 67:280–287

    PubMed  CAS  Google Scholar 

  • Kondo I, Marvizon JC, Song B, Salgado F, Codeluppi S, Hua XY, Yaksh TL (2005) Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release. J Neurosci 25:3651–3660

    PubMed  CAS  Google Scholar 

  • Kopf A, Schmidt S, Stein C (2006) Topical administration of analgesics. In: Bruera E, Higginson IJ, Ripamonti C, von Gunten CF (eds) Textbook of palliative medicine. Hodder Arnold, London, pp 450–457

    Google Scholar 

  • Kraus J, Borner C, Giannini E, Hickfang K, Braun H, Mayer P, Hoehe MR, Ambrosch A, Konig W, Höllt V (2001) Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site. J Biol Chem 276:43901–43908

    PubMed  CAS  Google Scholar 

  • Kyrkanides S, Fiorentino PM, Miller JN, Gan Y, Lai YC, Shaftel SS, Puzas JE, Piancino MG, O'Banion MK, Tallents RH (2007) Amelioration of pain and histopathologic joint abnormalities in the Col1-IL-1beta(XAT) mouse model of arthritis by intraarticular induction of mu-opioid receptor into the temporomandibular joint. Arthritis Rheum 56:2038–2048

    PubMed  CAS  Google Scholar 

  • Labuz D, Berger S, Mousa SA, Zöllner C, Rittner HL, Shaqura MA, Segovia-Silvestre T, Przewlocka B, Stein C, Machelska H (2006) Peripheral antinociceptive effects of exogenous and immune cell-derived endomorphins in prolonged inflammatory pain. J Neurosci 26:4350–4358

    PubMed  CAS  Google Scholar 

  • Labuz D, Mousa SA, Schafer M, Stein C, Machelska H (2007) Relative contribution of peripheral versus central opioid receptors to antinociception. Brain Res 1160:30–38

    PubMed  CAS  Google Scholar 

  • LaMendola J, Martin SK, Steiner DF (1997) Expression of PC3, carboxypeptidase E and enkephalin in human monocyte-derived macrophages as a tool for genetic studies. FEBS Lett 404:19–22

    PubMed  CAS  Google Scholar 

  • Law PY, Wong YH, Loh HH (2000) Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 40:389–430

    PubMed  CAS  Google Scholar 

  • Ledford H (2007) Fever pitch. Nature 450:600–601

    PubMed  CAS  Google Scholar 

  • Li JL, Kaneko T, Mizuno N (1996) Effects of peripheral nerve ligation on expression of mu-opioid receptor in sensory ganglion neurons: an immunohistochemical study in dorsal root and nodose ganglion neurons of the rat. Neurosci Lett 214:91–94

    PubMed  CAS  Google Scholar 

  • Li JL, Ding YQ, Li YQ, Li JS, Nomura S, Kaneko T, Mizuno N (1998) Immunocytochemical localization of mu-opioid receptor in primary afferent neurons containing substance P or calcitonin gene-related peptide. A light and electron microscope study in the rat. Brain Res 794:347–352

    CAS  Google Scholar 

  • Likar R, Schäfer M, Paulak F, Sittl R, Pipam W, Schalk H, Geissler D, Bernatzky G (1997) Intraarticular morphine analgesia in chronic pain patients with osteoarthritis. Anesth Analg 84:1313–1317

    PubMed  CAS  Google Scholar 

  • Likar R, Mousa SA, Philippitsch G, Steinkellner H, Koppert W, Stein C, Schäfer M (2004) Increased numbers of opioid expressing inflammatory cells do not affect intra-articular morphine analgesia. Br J Anaesth 93:375–380

    PubMed  CAS  Google Scholar 

  • Likar R, Mousa SA, Steinkellner H, Koppert W, Philippitsch G, Stein C, Schafer M (2007) Involvement of intra-articular corticotropin-releasing hormone in postoperative pain modulation. Clin J Pain 23:136–142

    PubMed  Google Scholar 

  • Lyons PD, Blalock JE (1997) Pro-opiomelanocortin gene expression and protein processing in rat mononuclear leukocytes. J Neuroimmunol 78:47–56

    PubMed  CAS  Google Scholar 

  • Machelska H (2007) Targeting of opioid-producing leukocytes for pain control. Neuropeptides 41:355–363

    PubMed  CAS  Google Scholar 

  • Machelska H, Cabot PJ, Mousa SA, Zhang Q, Stein C (1998) Pain control in inflammation governed by selectins. Nat Med 4:1425–1428

    PubMed  CAS  Google Scholar 

  • Machelska H, Pflüger M, Weber W, Piranvisseh-Volk M, Daubert JD, Dehaven R, Stein C (1999) Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans. J Pharmacol Exp Ther 290:354–361

    PubMed  CAS  Google Scholar 

  • Machelska H, Mousa SA, Brack A, Schopohl JK, Rittner HL, Schäfer M, Stein C (2002) Opioid control of inflammatory pain regulated by intercellular adhesion molecule-1. J Neurosci 22:5588–5596

    PubMed  CAS  Google Scholar 

  • Machelska H, Schopohl JK, Mousa SA, Labuz D, Schafer M, Stein C (2003) Different mechanisms of intrinsic pain inhibition in early and late inflammation. J Neuroimmunol 141:30–39

    PubMed  CAS  Google Scholar 

  • Machelska H, Brack A, Mousa SA, Schopohl JK, Rittner HL, Schafer M, Stein C (2004) Selectins and integrins but not platelet-endothelial cell adhesion molecule-1 regulate opioid inhibition of inflammatory pain. Br J Pharmacol 142:772–780

    PubMed  CAS  Google Scholar 

  • Mansour A, Fox CA, Burke S, Meng F, Thompson RC, Akil H, Watson SJ (1994) Mu, delta, and kappa-opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J Comp Neurol 350:412–438

    PubMed  CAS  Google Scholar 

  • Martin-Schild S, Gerall AA, Kastin AJ, Zadina JE (1998) Endomorphin-2 is an endogenous opioid in primary sensory afferent fibers. Peptides 19:1783–1789

    PubMed  CAS  Google Scholar 

  • Mata M, Glorioso JC, Fink DJ (2002) Targeted gene delivery to the nervous system using herpes simplex virus vectors. Physiol Behav 77:483–488

    PubMed  CAS  Google Scholar 

  • Meng F, Xie GX, Thompson RC, Mansour A, Goldstein A, Watson SJ, Akil H (1993) Cloning and pharmacological characterization of a rat kappa-opioid receptor. Proc Natl Acad Sci USA 90:9954–9958

    PubMed  CAS  Google Scholar 

  • Minami M, Maekawa K, Yabuuchi K, Satoh M (1995) Double in situ hybridization study on coexistence of mu-, delta- and kappa-opioid receptor mRNAs with preprotachykinin A mRNA in the rat dorsal root ganglia. Brain Res Mol Brain Res 30:203–210

    PubMed  CAS  Google Scholar 

  • Mousa SA, Schäfer M, Mitchell WM, Hassan AHS, Stein C (1996) Local upregulation of corticotropin- releasing hormone and interleukin-1 receptors in rats with painful hindlimb inflammation. Eur J Pharmacol 311:221–231

    PubMed  CAS  Google Scholar 

  • Mousa SA, Machelska H, Schäfer M, Stein C (2000) Co-expression of beta-endorphin with adhesion molecules in a model of inflammatory pain. J Neuroimmunol 108:160–170

    PubMed  CAS  Google Scholar 

  • Mousa SA, Zhang Q, Sitte N, Ji R, Stein C (2001) beta-Endorphin-containing memory-cells and mu-opioid receptors undergo transport to peripheral inflamed tissue. J Neuroimmunol 115:71–78

    PubMed  CAS  Google Scholar 

  • Mousa SA, Machelska H, Schäfer M, Stein C (2002) Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J Neuroimmunol 126:5–15

    PubMed  CAS  Google Scholar 

  • Mousa SA, Bopaiah CP, Stein C, Schafer M (2003) Involvement of corticotropin-releasing hormone receptor subtypes 1 and 2 in peripheral opioid-mediated inhibition of inflammatory pain. Pain 106:297–307

    PubMed  CAS  Google Scholar 

  • Mousa SA, Shakibaei M, Sitte N, Schäfer M, Stein C (2004) Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. Endocrinology 145:1331–1341

    PubMed  CAS  Google Scholar 

  • Mousa SA, Straub RH, Schafer M, Stein C (2007a) Beta-endorphin, Met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis. Ann Rheum Dis 66:871–879

    PubMed  CAS  Google Scholar 

  • Mousa SA, Cheppudira BP, Shaqura M, Fischer O, Hofmann J, Hellweg R, Schafer M (2007b) Nerve growth factor governs the enhanced ability of opioids to suppress inflammatory pain. Brain 130:502–513

    PubMed  Google Scholar 

  • Obara I, Makuch W, Spetea M, Schutz J, Schmidhammer H, Przewlocki R, Przewlocka B (2007) Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat. Eur J Pharmacol 558:60–67

    PubMed  CAS  Google Scholar 

  • Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller RJ (2001) Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 21:5027–5035

    PubMed  CAS  Google Scholar 

  • Patwardhan AM, Berg KA, Akopain AN, Jeske NA, Gamper N, Clarke WP, Hargreaves KM (2005) Bradykinin-induced functional competence and trafficking of the delta-opioid receptor in trigeminal nociceptors. J Neurosci 25:8825–8832

    PubMed  CAS  Google Scholar 

  • Philippe D, Dubuquoy L, Groux H, Brun V, Chuoi-Mariot MT, Gaveriaux-Ruff C, Colombel JF, Kieffer BL, Desreumaux P (2003) Anti-inflammatory properties of the mu-opioid receptor support its use in the treatment of colon inflammation. J Clin Invest 111:1329–1338

    PubMed  CAS  Google Scholar 

  • Picard PR, Tramer MR, McQuay HJ, Moore RA (1997) Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 72:309–318

    PubMed  CAS  Google Scholar 

  • Pierce TL, Grahek MD, Wessendorf MW (1998) Immunoreactivity for endomorphin-2 occurs in primary afferents in rats and monkey. Neuroreport 9:385–389

    PubMed  CAS  Google Scholar 

  • Pohl M, Collin E, Bourgoin S, Conrath M, Benoliel JJ, Nevo I, Hamon M, Giraud P, Cesselin F (1994) Expression of preproenkephalin A gene and presence of Met-enkephalin in dorsal root ganglia of the adult rat. J Neurochem 63:1226–1234

    PubMed  CAS  Google Scholar 

  • Pohl M, Meunier A, Hamon M, Braz J (2003) Gene therapy of chronic pain. Curr Gene Ther 3:223–238

    PubMed  CAS  Google Scholar 

  • Pol O, Murtra P, Caracuel L, Valverde O, Puig MM, Maldonado R (2006) Expression of opioid receptors and c-fos in CB1 knockout mice exposed to neuropathic pain. Neuropharmacology 50:123–132

    PubMed  CAS  Google Scholar 

  • Polydefkis M, Griffin JW, McArthur J (2003) New insights into diabetic polyneuropathy. JAMA 290:1371–1376

    PubMed  CAS  Google Scholar 

  • Przewlocki R, Gramsch C, Pasi A, Herz A (1983) Characterization and localization of immunoreactive dynorphin, alpha-neoendorphin, met-enkephalin and substance P in human spinal cord. Brain Res 280:95–103

    PubMed  CAS  Google Scholar 

  • Przewlocki R, Hassan AHS, Lason W, Epplen C, Herz A, Stein C (1992) Gene expression and localization of opioid peptides in immune cells of inflamed tissue. Functional role in antinociception. Neuroscience 48:491–500

    CAS  Google Scholar 

  • Pühler W, Zollner C, Brack A, Shaqura MA, Krause H, Schafer M, Stein C (2004) Rapid upregulation of mu-opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation depends on neuronal conduction. Neuroscience 129:473–479

    Google Scholar 

  • Pühler W, Rittner HL, Mousa SA, Brack A, Krause H, Stein C, Schafer M (2006) Interleukin-1 beta contributes to the upregulation of kappa-opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation. Neuroscience 141:989–998

    Google Scholar 

  • Quartu M, Del Fiacco M (1994) Enkephalins occur and colocalize with substance P in human trigeminal ganglion neurones. Neuroreport 5:465–468

    PubMed  CAS  Google Scholar 

  • Rasenick MM, Childers SR (1989) Modification of Gs-stimulated adenylate cyclase in brain membranes by low pH pretreatment: correlation with altered guanine nucleotide exchange. J Neurochem 53:219–225

    PubMed  CAS  Google Scholar 

  • Rashid MH, Inoue M, Toda K, Ueda H (2004) Loss of peripheral morphine analgesia contributes to the reduced effectiveness of systemic morphine in neuropathic pain. J Pharmacol Exp Ther 309:380–387

    PubMed  CAS  Google Scholar 

  • Rau KK, Caudle RM, Cooper BY, Johnson RD (2005) Diverse immunocytochemical expression of opioid receptors in electrophysiologically defined cells of rat dorsal root ganglia. J Chem Neuroanat 29:255–264

    PubMed  CAS  Google Scholar 

  • Reichert JA, Daughters RS, Rivard R, Simone DA (2001) Peripheral and preemptive opioid antinociception in a mouse visceral pain model. Pain 89:221–227

    PubMed  CAS  Google Scholar 

  • Rittner HL, Brack A, Machelska H, Mousa SA, Bauer M, Schäfer M, Stein C (2001) Opioid peptide-expressing leukocytes: identification, recruitment, and simultaneously increasing inhibition of inflammatory pain. Anesthesiology 95:500–508

    PubMed  CAS  Google Scholar 

  • Rittner HL, Machelska H, Stein C (2005) Leukocytes in the regulation of pain and analgesia. J Leukoc Biol 78:1215–1222

    PubMed  CAS  Google Scholar 

  • Rittner HL, Mousa SA, Labuz D, Beschmann K, Schafer M, Stein C, Brack A (2006a) Selective local PMN recruitment by CXCL1 or CXCL2/3 injection does not cause inflammatory pain. J Leukoc Biol 79:1022–1032

    PubMed  CAS  Google Scholar 

  • Rittner HL, Labuz D, Schaefer M, Mousa SA, Schulz S, Schafer M, Stein C, Brack A (2006b) Pain control by CXCR2 ligands through Ca2+-regulated release of opioid peptides from polymorphonuclear cells. FASEB J 20:2627–2629

    PubMed  CAS  Google Scholar 

  • Rittner HL, Lux C, Labuz D, Mousa SA, Schafer M, Stein C, Brack A (2007a) Neurokinin-1 receptor antagonists inhibit the recruitment of opioid-containing leukocytes and impair peripheral antinociception. Anesthesiology 107:1009–1017

    PubMed  CAS  Google Scholar 

  • Rittner HL, Labuz D, Richter JF, Brack A, Schafer M, Stein C, Mousa SA (2007b) CXCR1/2 ligands induce p38 MAPK-dependent translocation and release of opioid peptides from primary granules in vitro and in vivo. Brain Behav Immun 21:1021–1032

    PubMed  CAS  Google Scholar 

  • Rittner HL, Brack A, Stein C (2008) The other side of the medal: How chemokines promote analgesia. Neurosci Lett 437:203–208

    PubMed  CAS  Google Scholar 

  • Riviere PJ (2004) Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol 141:1331–1334

    PubMed  CAS  Google Scholar 

  • Sawynok J (2003) Topical and peripherally acting analgesics. Pharmacol Rev 55:1–20

    PubMed  CAS  Google Scholar 

  • Schäfer M, Carter L, Stein C (1994) Interleukin-1β and corticotropin-releasing-factor inhibit pain by releasing opioids from immune cells in inflamed tissue. Proc Natl Acad Sci USA 91:4219–4223

    PubMed  Google Scholar 

  • Schäfer M, Mousa SA, Zhang Q, Carter L, Stein C (1996) Expression of corticotropin-releasing factor in inflamed tissue is required for intrinsic peripheral opioid analgesia. Proc Natl Acad Sci USA 93:6096–6100

    PubMed  Google Scholar 

  • Schmitt TK, Mousa SA, Brack A, Schmidt DK, Rittner HL, Welte M, Schäfer M, Stein C (2003) Modulation of peripheral endogenous opioid analgesia by central afferent blockade. Anesthesiology 98:195–202

    PubMed  CAS  Google Scholar 

  • Selley DE, Breivogel CS, Childers SR (1993) Modification of G protein-coupled functions by low pH pretreatment of membranes from NG108-15 cells: increase in opioid agonist efficacy by decreased inactivation of G proteins. Mol Pharmacol 44:731–741

    PubMed  CAS  Google Scholar 

  • Shannon HE, Lutz EA (2002) Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats. Neuropharmacology 42:253–261

    PubMed  CAS  Google Scholar 

  • Shaqura MA, Zöllner C, Mousa SA, Stein C, Schäfer M (2004) Characterization of mu-opioid receptor binding and G protein coupling in rat hypothalamus, spinal cord, and primary afferent neurons during inflammatory pain. J Pharmacol Exp Ther 308:712–718

    PubMed  CAS  Google Scholar 

  • Silbert SC, Beacham DW, McCleskey EW (2003) Quantitative single-cell differences in mu-opioid receptor mRNA distinguish myelinated and unmyelinated nociceptors. J Neurosci 23:34–42

    PubMed  CAS  Google Scholar 

  • Sitte N, Busch M, Mousa SA, Labuz D, Rittner H, Gore C, Krause H, Stein C, Schafer M (2007) Lymphocytes upregulate signal sequence-encoding proopiomelanocortin mRNA and beta-endorphin during painful inflammation in vivo. J Neuroimmunol 183:133–145

    PubMed  CAS  Google Scholar 

  • Smith EM (2003) Opioid peptides in immune cells. Adv Exp Med Biol 521:51–68

    PubMed  CAS  Google Scholar 

  • Ständer S, Gunzer M, Metze D, Luger T, Steinhoff M (2002) Localization of mu-opioid receptor 1A on sensory nerve fibers in human skin. Regul Pept 110:75–83

    PubMed  Google Scholar 

  • Stein C (1993) Peripheral mechanisms of opioid analgesia. Anesth Analg 76:182–191

    PubMed  CAS  Google Scholar 

  • Stein C (1995) The control of pain in peripheral tissue by opioids. N Engl J Med 332:1685–1690

    PubMed  CAS  Google Scholar 

  • Stein C, Millan MJ, Shippenberg TS, Peter K, Herz A (1989) Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 248:1269–1275

    CAS  Google Scholar 

  • Stein C, Gramsch C, Herz A (1990a) Intrinsic mechanisms of antinociception in inflammation. Local opioid receptors and β-endorphin. J Neurosci 10:1292–1298

    CAS  Google Scholar 

  • Stein C, Hassan AH, Przewlocki R, Gramsch C, Peter K, Herz A (1990b) Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA 87:5935–5939

    PubMed  CAS  Google Scholar 

  • Stein C, Comisel K, Haimerl E, Yassouridis A, Lehrberger K, Herz A, Peter K (1991) Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N Engl J Med 325:1123–1126

    PubMed  CAS  Google Scholar 

  • Stein C, Hassan AHS, Lehrberger K, Giefing J, Yassouridis A (1993) Local analgesic effect of endogenous opioid peptides. Lancet 342:321–324

    PubMed  CAS  Google Scholar 

  • Stein C, Pflüger M, Yassouridis A, Hoelzl J, Lehrberger K, Welte C, Hassan AHS (1996) No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest 98:793–799

    PubMed  CAS  Google Scholar 

  • Stein A, Yassouridis A, Szopko C, Helmke K, Stein C (1999) Intraarticular morphine versus dexamethasone in chronic arthritis. Pain 83:525–532

    PubMed  CAS  Google Scholar 

  • Stein C, Machelska H, Schäfer M (2001) Peripheral analgesic and anti-inflammatory effects of opioids. Z Rheumatol 60:416–424

    PubMed  CAS  Google Scholar 

  • Stein C, Schäfer M, Machelska H (2003) Attacking pain at its source: new perspectives on opioids. Nat Med 9:1003–1008

    PubMed  CAS  Google Scholar 

  • Sternini C, Spann M, Anton B, Keith DE Jr, Bunnett NW, von Zastrow M, Evans C, Brecha NC (1996) Agonist-selective endocytosis of mu-opioid receptor by neurons in vivo. Proc Natl Acad Sci USA 93:9241–9246

    PubMed  CAS  Google Scholar 

  • Straub RH, Wolff C, Fassold A, Hofbauer R, Chover-Gonzalez A, Richards LJ, Jessop DS (2008) Anti-inflammatory role of endomorphins in osteoarthritis, rheumatoid arthritis, and adjuvant-induced polyarthritis. Arthritis Rheum 58:456–466

    PubMed  CAS  Google Scholar 

  • Sweetnam PM, Wrathall JR, Neale JH (1986) Localization of dynorphin gene product-immunoreactivity in neurons from spinal cord and dorsal root ganglia. Neuroscience 18:947–955

    PubMed  CAS  Google Scholar 

  • Szabo I, Chen XH, Xin L, Adler MW, Howard OM, Oppenheim JJ, Rogers TJ (2002) Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. Proc Natl Acad Sci USA 99:10276–10281

    PubMed  CAS  Google Scholar 

  • Tegeder I, Geisslinger G (2004) Opioids as modulators of cell death and survival--unraveling mechanisms and revealing new indications. Pharmacol Rev 56:351–369

    PubMed  CAS  Google Scholar 

  • Tegeder I, Meier S, Burian M, Schmidt H, Geisslinger G, Lotsch J (2003) Peripheral opioid analgesia in experimental human pain models. Brain 126:1092–1102

    PubMed  Google Scholar 

  • Terman GW, Shavit Y, Lewis JW, Cannon JT, Liebeskind JC (1984) Intrinsic mechanisms of pain inhibition: activation by stress. Science 226:1270–1277

    PubMed  CAS  Google Scholar 

  • Truong W, Cheng C, Xu QG, Li XQ, Zochodne DW (2003) Mu-opioid receptors and analgesia at the site of a peripheral nerve injury. Ann Neurol 53:366–375

    PubMed  CAS  Google Scholar 

  • Verma-Gandhu M, Bercik P, Motomura Y, Verdu EF, Khan WI, Blennerhassett PA, Wang L, El-Sharkawy RT, Collins SM (2006) CD4+ T-cell modulation of visceral nociception in mice. Gastroenterology 130:1721–1728

    PubMed  CAS  Google Scholar 

  • Vetter I, Kapitzke D, Hermanussen S, Monteith GR, Cabot PJ (2006) The effects of pH on beta-endorphin and morphine inhibition of calcium transients in dorsal root ganglion neurons. J Pain 7:488–499

    PubMed  CAS  Google Scholar 

  • Vindrola O, Mayer AMS, Citera G, Spitzer JA, Espinoza LR (1994) Prohormone convertases PC2 and PC3 in rat neutrophils and macrophages. Neuropeptides 27:235–244

    PubMed  CAS  Google Scholar 

  • von Andrian UH, Mackay CR (2000) T-cell function and migration. Two sides of the same coin. N Engl J Med 343:1020–1034

    CAS  Google Scholar 

  • Walczak JS, Pichette V, Leblond F, Desbiens K, Beaulieu P (2005) Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain. Neuroscience 132:1093–1102

    PubMed  CAS  Google Scholar 

  • Wang H, Wessendorf MW (2001) Equal proportions of small and large DRG neurons express opioid receptor mRNAs. J Comp Neurol 429:590–600

    PubMed  CAS  Google Scholar 

  • Wang JB, Imai Y, Eppler CM, Gregor P, Spivak CE, Uhl GR (1993) Mu-opiate receptor: cDNA cloning and expression. Proc Natl Acad Sci USA 90:10230–10234

    PubMed  CAS  Google Scholar 

  • Weihe E, Hartschuh W, Weber E (1985) Prodynorphin opioid peptides in small somatosensory primary afferents of guinea pig. Neurosci Lett 58:347–352

    PubMed  CAS  Google Scholar 

  • Wenk HN, Honda CN (1999) Immunohistochemical localization of delta-opioid receptors in peripheral tissues. J Comp Neurol 408:567–579

    PubMed  CAS  Google Scholar 

  • Whistler JL, Enquist J, Marley A, Fong J, Gladher F, Tsuruda P, Murray SR, Von Zastrow M (2002) Modulation of postendocytic sorting of G protein-coupled receptors. Science 297:615–620

    PubMed  CAS  Google Scholar 

  • Willer JC, Dehen H, Cambier J (1981) Stress-induced analgesia in humans: endogenous opioids and naloxone-reversible depression of pain reflexes. Science 212:689–691

    PubMed  CAS  Google Scholar 

  • Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288: 1765–1769

    PubMed  CAS  Google Scholar 

  • Yaksh TL (1988) Substance P release from knee joint afferent terminals: modulation by opioids. Brain Res 458:319–324

    PubMed  CAS  Google Scholar 

  • Zhang Q, Schäfer M, Elde R, Stein C (1998a) Effects of neurotoxins and hindpaw inflammation on opioid receptor immunoreactivities in dorsal root ganglia. Neuroscience 85:281–291

    PubMed  CAS  Google Scholar 

  • Zhang X, Bao L, Arvidsson U, Elde R, Hökfelt T (1998b) Localization and regulation of the delta-opioid receptor in dorsal root ganglia and spinal cord of the rat and monkey: evidence for association with the membrane of large dense-core vesicles. Neuroscience 82:1225–1242

    PubMed  CAS  Google Scholar 

  • Zhang X, Bao L, Shi TJ, Ju G, Elde R, Hökfelt T (1998c) Down-regulation of mu-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy. Neuroscience 82:223–240

    PubMed  CAS  Google Scholar 

  • Zhang X, Bao L, Guan JS (2006) Role of delivery and trafficking of delta-opioid peptide receptors in opioid analgesia and tolerance. Trends Pharmacol Sci 27:324–329

    PubMed  CAS  Google Scholar 

  • Zhou L, Zhang Q, Stein C, Schðfer M (1998) Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. J Pharmacol Exp Ther 286(2):1000–1006

    Google Scholar 

  • Zhu Y, Hsu MS, Pintar JE (1998) Developmental expression of the mu-, kappa-, and delta-opioid receptor mRNAs in mouse. J Neurosci 18:2538–2549

    PubMed  CAS  Google Scholar 

  • Zöllner C, Stein C (2007) Opioids. Handb Exp Pharmacol 177:31–63

    PubMed  Google Scholar 

  • Zöllner C, Shaqura MA, Bopaiah CP, Mousa SA, Stein C, Schäfer M (2003) Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol Pharmacol 64:202–210

    PubMed  Google Scholar 

  • Zöllner C, Mousa SA, Fischer O, Rittner HL, Shaqura M, Brack A, Shakibaei M, Binder W, Urban F, Stein C, Schäfer M (2008) Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J Clin Invest 118:1065–1073

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemein-schaft (KFO 100) and the International Anesthesia Research Society.

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  1. Klinik für Anaesthesiologie und operative Intensivmedizin, Freie Universität Berlin, Charité – Campus Benjamin Franklin, 12200, Berlin, Germany

    Christoph Stein

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  1. Christoph Stein
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  2. Christian Zöllner
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Correspondence to Christoph Stein .

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  1. Dept. Medicine, Johns Hopkins Asthma & Allergy Center, Hopkins Bayview Circle 5501, Baltimore, 21224, U.S.A.

    Brendan J. Canning

  2. School of Biomedical & Health Sciences, King's College London, Guy's Campus, London, SE1 9RT, United Kingdom

    Domenico Spina

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Stein, C., Zöllner, C. (2009). Opioids and Sensory Nerves. In: Canning, B., Spina, D. (eds) Sensory Nerves. Handbook of Experimental Pharmacology, vol 194. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-79090-7_14

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