Skip to main content
SpringerLink
Log in

Delta Opioid Receptor Expression and Function in Primary Afferent Somatosensory Neurons

  • Chapter
  • First Online:
Book cover Delta Opioid Receptor Pharmacology and Therapeutic Applications

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 247))

Abstract

The functional diversity of primary afferent neurons of the dorsal root ganglia (DRG) generates a variety of qualitatively and quantitatively distinct somatosensory experiences, from shooting pain to pleasant touch. In recent years, the identification of dozens of genetic markers specifically expressed by subpopulations of DRG neurons has dramatically improved our understanding of this diversity and provided the tools to manipulate their activity and uncover their molecular identity and function. Opioid receptors have long been known to be expressed by discrete populations of DRG neurons, in which they regulate cell excitability and neurotransmitter release. We review recent insights into the identity of the DRG neurons that express the delta opioid receptor (DOR) and the ion channel mechanisms that DOR engages in these cells to regulate sensory input. We highlight recent findings derived from DORGFP reporter mice and from in situ hybridization and RNA sequencing studies in wild-type mice that revealed DOR presence in cutaneous mechanosensory afferents eliciting touch and implicated in tactile allodynia. Mechanistically, we describe how DOR modulates opening of voltage-gated calcium channels (VGCCs) to control glutamatergic neurotransmission between somatosensory neurons and postsynaptic neurons in the spinal cord dorsal horn. We additionally discuss other potential signaling mechanisms, including those involving potassium channels, which DOR may engage to fine tune somatosensation. We conclude by discussing how this knowledge may explain the analgesic properties of DOR agonists against mechanical pain and uncovers an unanticipated specialized function for DOR in cutaneous mechanosensation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Abraira VE, Ginty DD (2013) The sensory neurons of touch. Neuron 79:618–639

    CAS  PubMed  Google Scholar 

  • Acosta CG, Lopez HS (1999) Delta opioid receptor modulation of several voltage-dependent Ca(2+) currents in rat sensory neurons. J Neurosci 19:8337–8348

    CAS  PubMed  Google Scholar 

  • Afify EA, Khedr MM, Omar AG, Nasser SA (2013) The involvement of K(ATP) channels in morphine-induced antinociception and hepatic oxidative stress in acute and inflammatory pain in rats. Fundam Clin Pharmacol 27:623–631

    CAS  PubMed  Google Scholar 

  • Aguilar-Bryan L et al (1998) Toward understanding the assembly and structure of KATP channels. Physiol Rev 78:227–245

    CAS  PubMed  Google Scholar 

  • Al-Hasani R, Bruchas MR (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115:1363–1381

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alloui A et al (2006) TREK-1, a K+ channel involved in polymodal pain perception. EMBO J 25:2368–2376

    CAS  PubMed  PubMed Central  Google Scholar 

  • Altier C, Zamponi GW (2008) Signaling complexes of voltage-gated calcium channels and G protein-coupled receptors. J Recept Signal Transduct Res 28:71–81

    CAS  PubMed  Google Scholar 

  • Alvarez FJ, Kavookjian AM, Light AR (1992) Synaptic-interactions between gaba-immunoreactive profiles and the terminals of functionally defined myelinated nociceptors in the monkey and cat spinal-cord. J Neurosci 12:2901–2917

    CAS  PubMed  Google Scholar 

  • Arcourt A et al (2017) Touch receptor-derived sensory information alleviates acute pain signaling and fine-tunes nociceptive reflex coordination. Neuron 93:179–193

    CAS  PubMed  Google Scholar 

  • Arikkath J, Campbell KP (2003) Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr Opin Neurobiol 13:298–307

    CAS  PubMed  Google Scholar 

  • Arvidsson U et al (1995) Delta-opioid receptor immunoreactivity: distribution in brainstem and spinal cord, and relationship to biogenic amines and enkephalin. J Neurosci 15:1215–1235

    CAS  PubMed  Google Scholar 

  • Bai L et al (2015) Genetic identification of an expansive mechanoreceptor sensitive to skin stroking. Cell 163:1783–1795

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bao L et al (2003) Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron 37:121–133

    CAS  PubMed  Google Scholar 

  • Bardoni R et al (2014) Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn. Neuron 81:1312–1327

    CAS  PubMed  PubMed Central  Google Scholar 

  • Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bell TJ, Thaler C, Castiglioni AJ, Helton TD, Lipscombe D (2004) Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron 41:127–138

    CAS  PubMed  Google Scholar 

  • Biel M, Wahl-Schott C, Michalakis S, Zong X (2009) Hyperpolarization-activated cation channels: from genes to function. Physiol Rev 89:847–885

    CAS  PubMed  Google Scholar 

  • Brackley AD, Gomez R, Akopian AN, Henry MA, Jeske NA (2016) GRK2 constitutively governs peripheral delta opioid receptor activity. Cell Rep 16:2686–2698

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brittain JM et al (2011) Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2)(+) channel complex. Nat Med 17:822–829

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brohawn SG, Su Z, MacKinnon R (2014) Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels. Proc Natl Acad Sci U S A 111:3614–3619

    CAS  PubMed  PubMed Central  Google Scholar 

  • Buraei Z, Yang J (2010) The ss subunit of voltage-gated Ca2+ channels. Physiol Rev 90:1461–1506

    CAS  PubMed  PubMed Central  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

    CAS  PubMed  Google Scholar 

  • Buzas B, Izenwasser S, Portoghese PS, Cox BM (1994) Evidence for delta opioid receptor subtypes regulating adenylyl cyclase activity in rat brain. Life Sci 54:PL101–PL106

    CAS  PubMed  Google Scholar 

  • Cahill CM et al (2001) Immunohistochemical distribution of delta opioid receptors in the rat central nervous system: evidence for somatodendritic labeling and antigen-specific cellular compartmentalization. J Comp Neurol 440:65–84

    CAS  PubMed  Google Scholar 

  • Cahill CM, Holdridge SV, Morinville A (2007) Trafficking of delta-opioid receptors and other G-protein-coupled receptors: implications for pain and analgesia. Trends Pharmacol Sci 28:23–31

    CAS  PubMed  Google Scholar 

  • Cahill CM, Walwyn W, Taylor AMW, Pradhan AAA, Evans CJ (2016) Allostatic mechanisms of opioid tolerance beyond desensitization and down regulation. Trends Pharmacol Sci 37:963–976

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cao CQ, Hong Y, Dray A, Perkins M (2001) Spinal delta-opioid receptors mediate suppression of systemic SNC80 on excitability of the flexor reflex in normal and inflamed rat. Eur J Pharmacol 418:79–87

    CAS  PubMed  Google Scholar 

  • Catterall WA (2011) Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 3:a003947

    PubMed  PubMed Central  Google Scholar 

  • Cavanaugh DJ et al (2009) Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci U S A 106:9075–9080

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cavanaugh DJ et al (2011) Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons. J Neurosci 31:10119–10127

    CAS  PubMed  PubMed Central  Google Scholar 

  • Charfi I, Audet N, Tudashki HB, Pineyro G (2015) Identifying ligand-specific signalling within biased responses: focus on delta opioid receptor ligands. Br J Pharmacol 172:435–448

    CAS  PubMed  Google Scholar 

  • Chneiweiss H, Glowinski J, Premont J (1988) Mu and delta opiate receptors coupled negatively to adenylate cyclase on embryonic neurons from the mouse striatum in primary cultures. J Neurosci 8:3376–3382

    CAS  PubMed  Google Scholar 

  • Chung MK et al (2014) Peripheral G protein-coupled inwardly rectifying potassium channels are involved in delta-opioid receptor-mediated anti-hyperalgesia in rat masseter muscle. Eur J Pain 18:29–38

    CAS  PubMed  Google Scholar 

  • Craig AD (2003) Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 26:1–30

    CAS  PubMed  Google Scholar 

  • Crain SM, Shen KF (1990) Opioids can evoke direct receptor-mediated excitatory effects on sensory neurons. Trends Pharmacol Sci 11:77–81

    CAS  PubMed  Google Scholar 

  • Cunha TM et al (2010) Morphine peripheral analgesia depends on activation of the PI3Kgamma/AKT/nNOS/NO/KATP signaling pathway. Proc Natl Acad Sci U S A 107:4442–4447

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dado RJ, Law PY, Hoh HH, Elde R (1993) Immunofluorescent indentification of a delta ([delta])-opioid receptor on primary afferent nerve terminals. Neuroreport 5:341–344

    CAS  PubMed  Google Scholar 

  • Dang VC, Christie MJ (2012) Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons. Br J Pharmacol 165:1704–1716

    CAS  PubMed  PubMed Central  Google Scholar 

  • De Schepper HU et al (2008) TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats. Am J Physiol Gastrointest Liver Physiol 294:G245–G253

    PubMed  Google Scholar 

  • Delfini MC et al (2013) TAFA4, a chemokine-like protein, modulates injury-induced mechanical and chemical pain hypersensitivity in mice. Cell Rep 5:378–388

    CAS  PubMed  Google Scholar 

  • Delmas P, Hao J, Rodat-Despoix L (2011) Molecular mechanisms of mechanotransduction in mammalian sensory neurons. Nat Rev Neurosci 12:139–153

    CAS  PubMed  Google Scholar 

  • Desmeules JA, Kayser V, Guilbaud G (1993) Selective opioid receptor agonists modulate mechanical allodynia in an animal model of neuropathic pain. Pain 53:277–285

    CAS  PubMed  Google Scholar 

  • Devilliers M et al (2013) Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nat Commun 4:2941

    PubMed  Google Scholar 

  • de Nooij JC, Doobar S, Jessell TM (2013) Etv1 inactivation reveals proprioceptor subclasses that reflect the level of NT3 expression in muscle targets. Neuron 77:1055–1068

    PubMed  PubMed Central  Google Scholar 

  • Du X, Wang C, Zhang H (2011) Activation of ATP-sensitive potassium channels antagonize nociceptive behavior and hyperexcitability of DRG neurons from rats. Mol Pain 7:35

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dussor G, Zylka MJ, Anderson DJ, McCleskey EW (2008) Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors. J Neurophysiol 99:1581–1589

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eckert WA III, Light AR (2002) Hyperpolarization of substantia gelatinosa neurons evoked by mu-, kappa-, delta 1-, and delta 2-selective opioids. J Pain 3:115–125

    PubMed  Google Scholar 

  • Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA (2011) HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 333:1462–1466

    CAS  PubMed  Google Scholar 

  • Emery EC et al (2016) In vivo characterization of distinct modality-specific subsets of somatosensory neurons using GCaMP. Sci Adv 2:e1600990

    PubMed  PubMed Central  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

    CAS  PubMed  Google Scholar 

  • Evans AR, Nicol GD, Vasko MR (1996) Differential regulation of evoked peptide release by voltage-sensitive calcium channels in rat sensory neurons. Brain Res 712:265–273

    CAS  PubMed  Google Scholar 

  • Eybalin M, Pujol R, Bockaert J (1987) Opioid receptors inhibit the adenylate cyclase in guinea pig cochleas. Brain Res 421:336–342

    CAS  PubMed  Google Scholar 

  • Fan SF, Shen KF, Crain SM (1993) Mu and delta-opioid agonists at low concentrations decrease voltage-dependent K+ currents in F11 neuroblastoma X drug neuron hybrid-cells via cholera toxin-sensitive receptors. Brain Res 605:214–220

    CAS  PubMed  Google Scholar 

  • Fatt P, Katz B (1953) The electrical properties of crustacean muscle fibres. J Physiol 120:171–204

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fields HL, Emson PC, Leigh BK, Gilbert RF, Iversen LL (1980) Multiple opiate receptor sites on primary afferent fibres. Nature 284:351–353

    CAS  PubMed  Google Scholar 

  • Filliol D et al (2000) Mice deficient for delta- and gamma-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 25:195–200

    CAS  PubMed  Google Scholar 

  • Franck MC et al (2011) Essential role of ret for defining non-peptidergic nociceptor phenotypes and functions in the adult mouse. Eur J Neurosci 33:1385–1400

    PubMed  Google Scholar 

  • François A et al (2017) A brainstem-spinal cord inhibitory circuit for mechanical pain modulation by GABA and enkephalins. Neuron 93(4):822–839.e6

    PubMed  Google Scholar 

  • Fuchs PN, Roza C, Sora I, Uhl G, Raja SN (1999) Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice. Brain Res 821:480–486

    CAS  PubMed  Google Scholar 

  • Fujita W, Gomes I, Devi LA (2014) Revolution in GPCR signalling: opioid receptor heteromers as novel therapeutic targets: IUPHAR review 10. Br J Pharmacol 171:4155–4176

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao XF, Zhang HL, You ZD, Lu CL, He C (2007) G protein-coupled inwardly rectifying potassium channels in dorsal root ganglion neurons. Acta Pharmacol Sin 28:185–190

    CAS  PubMed  Google Scholar 

  • Gaveriaux-Ruff C, Kieffer BL (2011) Delta opioid receptor analgesia: recent contributions from pharmacology and molecular approaches. Behav Pharmacol 22:405–414

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gaveriaux-Ruff C, Karchewski LA, Hever X, Matifas A, Kieffer BL (2008) Inflammatory pain is enhanced in delta opioid receptor-knockout mice. Eur J Neurosci 27:2558–2567

    PubMed  PubMed Central  Google Scholar 

  • Gaveriaux-Ruff C et al (2011) Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain 152:1238–1248

    CAS  PubMed  Google Scholar 

  • Gendron L et al (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

    CAS  PubMed  Google Scholar 

  • Gendron L, Mittal N, Beaudry H, Walwyn W (2015) Recent advances on the delta opioid receptor: from trafficking to function. Br J Pharmacol 172:403–419

    CAS  PubMed  Google Scholar 

  • Gendron L, Cahill CM, von Zastrow M, Schiller PW, Pineyro G (2016) Molecular pharmacology of delta-opioid receptors. Pharmacol Rev 68:631–700

    CAS  PubMed  PubMed Central  Google Scholar 

  • Georgoussi Z (2015) The other side of opioid receptor signaling: regulation by protein-protein interaction. Spring 4:L21

    Google Scholar 

  • Ghitani N et al (2017) Specialized mechanosensory nociceptors mediating rapid responses to hair pull. Neuron 95:944–954.e944

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gilman AG (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56:615–649

    CAS  PubMed  Google Scholar 

  • Glaum SR, Miller RJ, Hammond DL (1994) Inhibitory actions of delta 1-, delta 2-, and mu-opioid receptor agonists on excitatory transmission in lamina II neurons of adult rat spinal cord. J Neurosci 14:4965–4971

    CAS  PubMed  Google Scholar 

  • Goody RJ, Oakley SM, Filliol D, Kieffer BL, Kitchen I (2002) Quantitative autoradiographic mapping of opioid receptors in the brain of delta-opioid receptor gene knockout mice. Brain Res 945:9–19

    CAS  PubMed  Google Scholar 

  • Goswami SC et al (2014) Molecular signatures of mouse TRPV1-lineage neurons revealed by RNA-Seq transcriptome analysis. J Pain 15:1338–1359

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guan JS et al (2005) Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia. Cell 122:619–631

    CAS  PubMed  Google Scholar 

  • Gutierrez VP et al (2012) The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K(+) channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats. Behav Pharmacol 23:14–24

    CAS  PubMed  Google Scholar 

  • Gutierrez-Mecinas M, Watanabe M, Todd AJ (2014) Expression of gastrin-releasing peptide by excitatory interneurons in the mouse superficial dorsal horn. Mol Pain 10:79

    PubMed  PubMed Central  Google Scholar 

  • Heinke B, Balzer E, Sandkuhler J (2004) Pre- and postsynaptic contributions of voltage-dependent Ca2+ channels to nociceptive transmission in rat spinal lamina I neurons. Eur J Neurosci 19:103–111

    CAS  PubMed  Google Scholar 

  • Herlitze S, Hockerman GH, Scheuer T, Catterall WA (1997) Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel alpha1A subunit. Proc Natl Acad Sci U S A 94:1512–1516

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hervera A, Negrete R, Leanez S, Martin-Campos J, Pol O (2010) The role of nitric oxide in the local antiallodynic and antihyperalgesic effects and expression of delta-opioid and cannabinoid-2 receptors during neuropathic pain in mice. J Pharmacol Exp Ther 334:887–896

    CAS  PubMed  Google Scholar 

  • Hille B (1992) Ionic channels of excitable membranes, 2nd edn. Sinauer Associates, Inc., Sunderland, MA

    Google Scholar 

  • Holmseth S et al (2012) Specificity controls for immunocytochemistry: the antigen preadsorption test can lead to inaccurate assessment of antibody specificity. J Histochem Cytochem 60:174–187

    CAS  PubMed  PubMed Central  Google Scholar 

  • Honore E (2007) The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8:251–261

    CAS  PubMed  Google Scholar 

  • Hurley RW, Hammond DL (2000) The analgesic effects of supraspinal mu and delta opioid receptor agonists are potentiated during persistent inflammation. J Neurosci 20:1249–1259

    CAS  PubMed  Google Scholar 

  • Ikeda SR (1996) Voltage-dependent modulation of N-type calcium channels by G-protein beta gamma subunits. Nature 380:255–258

    CAS  PubMed  Google Scholar 

  • Izenwasser S, Buzas B, Cox BM (1993) Differential regulation of adenylyl cyclase activity by mu and delta opioids in rat caudate putamen and nucleus accumbens. J Pharmacol Exp Ther 267:145–152

    CAS  PubMed  Google Scholar 

  • Jankowski MP, Rau KK, Ekmann KM, Anderson CE, Koerber HR (2013) Comprehensive phenotyping of group III and IV muscle afferents in mouse. J Neurophysiol 109:2374–2381

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jelacic TM, Kennedy ME, Wickman K, Clapham DE (2000) Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3. J Biol Chem 275:36211–36216

    CAS  PubMed  Google Scholar 

  • Jiang YQ, Andrade A, Lipscombe D (2013) Spinal morphine but not ziconotide or gabapentin analgesia is affected by alternative splicing of voltage-gated calcium channel CaV2.2 pre-mRNA. Mol Pain 9:67

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jones RC III, Xu L, Gebhart GF (2005) The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid-sensing ion channel 3. J Neurosci 25:10981–10989

    CAS  PubMed  Google Scholar 

  • Joseph EK, Levine JD (2010) Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat. Neuroscience 171:344–350

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Kang D, Kim D (2006) TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. Am J Phys Cell Physiol 291:C138–C146

    CAS  Google Scholar 

  • Kawano T et al (2009a) ATP-sensitive potassium currents in rat primary afferent neurons: biophysical, pharmacological properties, and alterations by painful nerve injury. Neuroscience 162:431–443

    CAS  PubMed  Google Scholar 

  • Kawano T et al (2009b) Suppressed Ca2+/CaM/CaMKII-dependent K(ATP) channel activity in primary afferent neurons mediates hyperalgesia after axotomy. Proc Natl Acad Sci U S A 106:8725–8730

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kennedy ME, Nemec J, Clapham DE (1996) Localization and interaction of epitope-tagged GIRK1 and CIR inward rectifier K+ channel subunits. Neuropharmacology 35:831–839

    CAS  PubMed  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 U S A 89:12048–12052

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kitchen I, Slowe SJ, Matthes HW, Kieffer B (1997) Quantitative autoradiographic mapping of mu-, delta- and kappa-opioid receptors in knockout mice lacking the mu-opioid receptor gene. Brain Res 778:73–88

    CAS  PubMed  Google Scholar 

  • Koerber HR, Woodbury CJ (2002) Comprehensive phenotyping of sensory neurons using an ex vivo somatosensory system. Physiol Behav 77:589–594

    CAS  PubMed  Google Scholar 

  • Kolodziejczyk AA, Kim JK, Svensson V, Marioni JC, Teichmann SA (2015) The technology and biology of single-cell RNA sequencing. Mol Cell 58:610–620

    CAS  PubMed  Google Scholar 

  • Kouchek M, Takasusuki T, Terashima T, Yaksh TL, Xu Q (2013) Effects of intrathecal SNC80, a delta receptor ligand, on nociceptive threshold and dorsal horn substance p release. J Pharmacol Exp Ther 347:258–264

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lallemend F, Ernfors P (2012) Molecular interactions underlying the specification of sensory neurons. Trends Neurosci 35:373–381

    CAS  PubMed  Google Scholar 

  • Lamberts JT, Traynor JR (2013) Opioid receptor interacting proteins and the control of opioid signaling. Curr Pharm Design 19:7333–7347

    CAS  Google Scholar 

  • Law PY, Wu J, Koehler JE, Loh HH (1981) Demonstration and characterization of opiate inhibition of the striatal adenylate cyclase. J Neurochem 36:1834–1846

    CAS  PubMed  Google Scholar 

  • Lawson JJ, McIlwrath SL, Woodbury CJ, Davis BM, Koerber HR (2008) TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat. J Pain 9:298–308

    CAS  PubMed  PubMed Central  Google Scholar 

  • Le Bourdonnec B et al (2009) Spirocyclic delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4′-piperidine]-4-yl) benzamide (ADL5747). J Med Chem 52:5685–5702

    PubMed  Google Scholar 

  • Le Pichon CE, Chesler AT (2014) The functional and anatomical dissection of somatosensory subpopulations using mouse genetics. Front Neuroanat 8:21

    PubMed  PubMed Central  Google Scholar 

  • Lesage F et al (1995) Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J Biol Chem 270:28660–28667

    CAS  PubMed  Google Scholar 

  • Lewin GR, Moshourab R (2004) Mechanosensation and pain. J Neurobiol 61:30–44

    PubMed  Google Scholar 

  • Li L et al (2011) The functional organization of cutaneous low-threshold mechanosensory neurons. Cell 147:1615–1627

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Ma Q (2011) Generation of somatic sensory neuron diversity and implications on sensory coding. Curr Opin Neurobiol 21:52–60

    PubMed  Google Scholar 

  • Liu Q et al (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139:1353–1365

    PubMed  PubMed Central  Google Scholar 

  • Lumpkin EA, Bautista DM (2005) Feeling the pressure in mammalian somatosensation. Curr Opin Neurobiol 15:382–388

    CAS  PubMed  PubMed Central  Google Scholar 

  • Luo W et al (2007) A hierarchical NGF signaling cascade controls ret-dependent and ret-independent events during development of nonpeptidergic DRG neurons. Neuron 54:739–754

    CAS  PubMed  Google Scholar 

  • Luo W, Enomoto H, Rice FL, Milbrandt J, Ginty DD (2009) Molecular identification of rapidly adapting mechanoreceptors and their developmental dependence on ret signaling. Neuron 64:841–856

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ma Q (2010) Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest 120:3773–3778

    CAS  PubMed  PubMed Central  Google Scholar 

  • Makman MH, Dvorkin B, Crain SM (1988) Modulation of adenylate cyclase activity of mouse spinal cord-ganglion explants by opioids, serotonin and pertussis toxin. Brain Res 445:303–313

    CAS  PubMed  Google Scholar 

  • Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1987) Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci 7:2445–2464

    CAS  PubMed  Google Scholar 

  • Mark MD, Herlitze S (2000) G-protein mediated gating of inward-rectifier K+ channels. Eur J Biochem 267:5830–5836

    CAS  PubMed  Google Scholar 

  • Mennicken F et al (2003) Phylogenetic changes in the expression of delta opioid receptors in spinal cord and dorsal root ganglia. J Comp Neurol 465:349–360

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Mittal N et al (2013) Select G-protein-coupled receptors modulate agonist-induced signaling via a ROCK, LIMK, and beta-arrestin 1 pathway. Cell Rep 5:1010–1021

    CAS  PubMed  Google Scholar 

  • Moises HC, Rusin KI, Macdonald RL (1994) Mu- and kappa-opioid receptors selectively reduce the same transient components of high-threshold calcium current in rat dorsal root ganglion sensory neurons. J Neurosci 14:5903–5916

    CAS  PubMed  Google Scholar 

  • Momin A, Cadiou H, Mason A, McNaughton PA (2008) Role of the hyperpolarization-activated current Ih in somatosensory neurons. J Physiol 586:5911–5929

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murakami M et al (2001) Distribution of various calcium channel alpha(1) subunits in murine DRG neurons and antinociceptive effect of omega-conotoxin SVIB in mice. Brain Res 903:231–236

    CAS  PubMed  Google Scholar 

  • Murali SS et al (2015) High-voltage-activated calcium current subtypes in mouse DRG neurons adapt in a subpopulation-specific manner after nerve injury. J Neurophysiol 113:1511–1519

    CAS  PubMed  Google Scholar 

  • Nestler EJ (2004) Historical review: molecular and cellular mechanisms of opiate and cocaine addiction. Trends Pharmacol Sci 25:210–218

    CAS  PubMed  Google Scholar 

  • Nockemann D et al (2013) The K(+) channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Mol Med 5:1263–1277

    CAS  PubMed  PubMed Central  Google Scholar 

  • Noel J et al (2009) The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. EMBO J 28:1308–1318

    CAS  PubMed  PubMed Central  Google Scholar 

  • Normandin A, Luccarini P, Molat JL, Gendron L, Dallel R (2013) Spinal mu and delta opioids inhibit both thermal and mechanical pain in rats. J Neurosci 33:11703–11714

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nowycky MC, Fox AP, Tsien RW (1985) Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316:440–443

    CAS  PubMed  Google Scholar 

  • Nozaki C et al (2012) Delta-opioid mechanisms for ADL5747 and ADL5859 effects in mice: analgesia, locomotion, and receptor internalization. J Pharmacol Exp Ther 342:799–807

    CAS  PubMed  PubMed Central  Google Scholar 

  • Obara I et al (2009) Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and inflammatory pain. Pain 141:283–291

    CAS  PubMed  Google Scholar 

  • Ocana M, Cendan CM, Cobos EJ, Entrena JM, Baeyens JM (2004) Potassium channels and pain: present realities and future opportunities. Eur J Pharmacol 500:203–219

    CAS  PubMed  Google Scholar 

  • Ohkubo T, Shibata M (1995) ATP-sensitive K+ channels mediate regulation of substance P release via the prejunctional histamine H3 receptor. Eur J Pharmacol 277:45–49

    CAS  PubMed  Google Scholar 

  • Olianas MC, Onali P (1995) Participation of delta opioid receptor subtypes in the stimulation of adenylyl cyclase activity in rat olfactory bulb. J Pharmacol Exp Ther 275:1560–1567

    CAS  PubMed  Google Scholar 

  • Otis V, Sarret P, Gendron L (2011) Spinal activation of delta opioid receptors alleviates cancer-related bone pain. Neuroscience 183:221–229

    CAS  PubMed  PubMed Central  Google Scholar 

  • Overland AC et al (2009) Protein kinase C mediates the synergistic interaction between agonists acting at alpha2-adrenergic and delta-opioid receptors in spinal cord. J Neurosci 29:13264–13273

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pacheco Dda F, Pacheco CM, Duarte ID (2012) Peripheral antinociception induced by delta-opioid receptors activation, but not mu- or kappa-, is mediated by Ca(2)(+)-activated cl(−) channels. Eur J Pharmacol 674:255–259

    PubMed  Google Scholar 

  • Pacheco DF, Duarte ID (2005) Delta-opioid receptor agonist SNC80 induces peripheral antinociception via activation of ATP-sensitive K+ channels. Eur J Pharmacol 512:23–28

    CAS  PubMed  Google Scholar 

  • Pan HL et al (2008) Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Ther 117:141–161

    CAS  PubMed  Google Scholar 

  • Pare M, Elde R, Mazurkiewicz JE, Smith AM, Rice FL (2001) The Meissner corpuscle revised: a multiafferented mechanoreceptor with nociceptor immunochemical properties. J Neurosci 21:7236–7246

    CAS  PubMed  Google Scholar 

  • Patwardhan AM et al (2006) PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor. Pain 125:114–124

    CAS  PubMed  Google Scholar 

  • Peier AM et al (2002) A TRP channel that senses cold stimuli and menthol. Cell 108:705–715

    CAS  PubMed  Google Scholar 

  • Pena-dos-Santos DR et al (2009) Activation of peripheral kappa/Delta opioid receptors mediates 15-deoxy-(Delta12,14)-prostaglandin J2 induced-antinociception in rat temporomandibular joint. Neuroscience 163:1211–1219

    CAS  PubMed  Google Scholar 

  • Pereira JC Jr, Alves RC (2011) The labelled-lines principle of the somatosensory physiology might explain the phantom limb phenomenon. Med Hypotheses 77:853–856

    PubMed  Google Scholar 

  • Pettinger L, Gigout S, Linley JE, Gamper N (2013) Bradykinin controls pool size of sensory neurons expressing functional delta-opioid receptors. J Neurosci 33:10762–10771

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pradhan AA et al (2009) In vivo delta opioid receptor internalization controls behavioral effects of agonists. PLoS One 4:e5425

    PubMed  PubMed Central  Google Scholar 

  • Pradhan AA, Befort K, Nozaki C, Gaveriaux-Ruff C, Kieffer BL (2011) The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci 32:581–590

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pradhan AA, Smith ML, Kieffer BL, Evans CJ (2012) Ligand-directed signalling within the opioid receptor family. Br J Pharmacol 167:960–969

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pradhan A, Smith M, McGuire B, Evans C, Walwyn W (2013) Chronic inflammatory injury results in increased coupling of delta opioid receptors to voltage-gated Ca2+ channels. Mol Pain 9:8

    CAS  PubMed  PubMed Central  Google Scholar 

  • Prather PL, Loh HH, Law PY (1994) Interaction of delta-opioid receptors with multiple G proteins: a non-relationship between agonist potency to inhibit adenylyl cyclase and to activate G proteins. Mol Pharmacol 45:997–1003

    CAS  PubMed  Google Scholar 

  • Price TJ, Flores CM (2007) Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse. J Pain 8:263–272

    CAS  PubMed  Google Scholar 

  • Raingo J, Castiglioni AJ, Lipscombe D (2007) Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors. Nat Neurosci 10:285–292

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rau KK et al (2009) Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors. J Neurosci 29:8612–8619

    CAS  PubMed  PubMed Central  Google Scholar 

  • Riedl MS et al (2009) Coexpression of alpha 2A-adrenergic and delta-opioid receptors in substance P-containing terminals in rat dorsal horn. J Comp Neurol 513:385–398

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rodrigues AR, Duarte ID (2000) The peripheral antinociceptive effect induced by morphine is associated with ATP-sensitive K(+) channels. Br J Pharmacol 129:110–114

    CAS  PubMed  PubMed Central  Google Scholar 

  • Roerig SC, Loh HH, Law PY (1992) Identification of three separate guanine nucleotide-binding proteins that interact with the delta-opioid receptor in NG108-15 neuroblastoma x glioma hybrid cells. Mol Pharmacol 41:822–831

    CAS  PubMed  Google Scholar 

  • Rogers H, Henderson G (1990) Activation of mu- and delta-opioid receptors present on the same nerve terminals depresses transmitter release in the mouse hypogastric ganglion. Br J Pharmacol 101:505–512

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saegusa H et al (2001) Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel. EMBO J 20:2349–2356

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saloman JL, Niu KY, Ro JY (2011) Activation of peripheral delta-opioid receptors leads to anti-hyperalgesic responses in the masseter muscle of male and female rats. Neuroscience 190:379–385

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sandkuhler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707–758

    PubMed  Google Scholar 

  • Sarantopoulos C, McCallum B, Sapunar D, Kwok WM, Hogan Q (2003) ATP-sensitive potassium channels in rat primary afferent neurons: the effect of neuropathic injury and gabapentin. Neurosci Lett 343:185–189

    CAS  PubMed  Google Scholar 

  • Scherrer G et al (2006) Knockin mice expressing fluorescent delta-opioid receptors uncover G protein-coupled receptor dynamics in vivo. Proc Natl Acad Sci U S A 103:9691–9696

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scherrer G et al (2009) Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 137:1148–1159

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schroeder JE, McCleskey EW (1993) Inhibition of Ca2+ currents by a mu-opioid in a defined subset of rat sensory neurons. J Neurosci 13:867–873

    CAS  PubMed  Google Scholar 

  • Schroeder JE, Fischbach PS, Zheng D, McCleskey EW (1991) Activation of mu opioid receptors inhibits transient high- and low-threshold Ca2+ currents, but spares a sustained current. Neuron 6:13–20

    CAS  PubMed  Google Scholar 

  • Scroggs RS, Fox AP (1992) Multiple Ca2+ currents elicited by action potential waveforms in acutely isolated adult rat dorsal root ganglion neurons. J Neurosci 12:1789–1801

    CAS  PubMed  Google Scholar 

  • Sculptoreanu A, Scheuer T, Catterall WA (1993) Voltage-dependent potentiation of L-type Ca2+ channels due to phosphorylation by cAMP-dependent protein kinase. Nature 364:240–243

    CAS  PubMed  Google Scholar 

  • Seal RP et al (2009) Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462:651–655

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shen KF, Crain SM (1989) Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture. Brain Res 491:227–242

    CAS  PubMed  Google Scholar 

  • Simms BA, Zamponi GW (2014) Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron 82:24–45

    CAS  PubMed  Google Scholar 

  • Sluka KA, Rohlwing JJ, Bussey RA, Eikenberry SA, Wilken JM (2002) Chronic muscle pain induced by repeated acid injection is reversed by spinally administered mu- and delta-, but not kappa-, opioid receptor agonists. J Pharmacol Exp Ther 302:1146–1150

    CAS  PubMed  Google Scholar 

  • Spahn V et al (2013) Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner. Pain 154:598–608

    CAS  PubMed  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-receptors, delta-receptors and kappa-receptors. J Pharmacol Exp Ther 248:1269–1275

    CAS  PubMed  Google Scholar 

  • Stewart PE, Hammond DL (1994) Activation of spinal delta-1 or delta-2 opioid receptors reduces carrageenan-induced hyperalgesia in the rat. J Pharmacol Exp Ther 268:701–708

    CAS  PubMed  Google Scholar 

  • Sudhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547

    PubMed  Google Scholar 

  • Tanabe T et al (1987) Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature 328:313–318

    CAS  PubMed  Google Scholar 

  • Tang T, Kiang JG, Cote T, Cox BM (1995) Opioid-induced increase in [Ca2+]i in ND8-47 neuroblastoma x dorsal root ganglion hybrid cells is mediated through G protein-coupled delta-opioid receptors and desensitized by chronic exposure to opioid. J Neurochem 65:1612–1621

    CAS  PubMed  Google Scholar 

  • Tumati S, Roeske WR, Vanderah TW, Varga EV (2010) Sustained morphine treatment augments prostaglandin E2-evoked calcitonin gene-related peptide release from primary sensory neurons in a PKA-dependent manner. Eur J Pharmacol 648:95–101

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tumati S, Roeske WR, Largent-Milnes TM, Vanderah TW, Varga EV (2011) Intrathecal PKA-selective siRNA treatment blocks sustained morphine-mediated pain sensitization and antinociceptive tolerance in rats. J Neurosci Methods 199:62–68

    CAS  PubMed  PubMed Central  Google Scholar 

  • Usoskin D et al (2015) Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci 18:145–153

    CAS  PubMed  Google Scholar 

  • Vanderah TW (2010) Delta and kappa opioid receptors as suitable drug targets for pain. Clin J Pain 26:S10–S15

    PubMed  Google Scholar 

  • Wada Y et al (2000) A region of the sulfonylurea receptor critical for a modulation of ATP-sensitive K(+) channels by G-protein betagamma-subunits. EMBO J 19:4915–4925

    CAS  PubMed  PubMed Central  Google Scholar 

  • Walwyn W et al (2005) Induction of delta opioid receptor function by up-regulation of membrane receptors in mouse primary afferent neurons. Mol Pharmacol 68:1688–1698

    CAS  PubMed  Google Scholar 

  • Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10:57–63

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang HB et al (2010) Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons. Proc Natl Acad Sci U S A 107:13117–13122

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weng X, Smith T, Sathish J, Djouhri L (2012) Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Adelta-nociceptors. Pain 153:900–914

    CAS  PubMed  Google Scholar 

  • Westenbroek RE, Hoskins L, Catterall WA (1998) Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals. J Neurosci 18:6319–6330

    CAS  PubMed  Google Scholar 

  • Wilson SM et al (2000) The status of voltage-dependent calcium channels in alpha 1E knock-out mice. J Neurosci 20:8566–8571

    CAS  PubMed  Google Scholar 

  • Wong YH et al (1991) Mutant alpha subunits of Gi2 inhibit cyclic AMP accumulation. Nature 351:63–65

    CAS  PubMed  Google Scholar 

  • Wong YH, Conklin BR, Bourne HR (1992) Gz-mediated hormonal inhibition of cyclic AMP accumulation. Science 255:339–342

    CAS  PubMed  Google Scholar 

  • Woodbury CJ, Kullmann FA, McIlwrath SL, Koerber HR (2008) Identity of myelinated cutaneous sensory neurons projecting to nocireceptive laminae following nerve injury in adult mice. J Comp Neurol 508:500–509

    PubMed  PubMed Central  Google Scholar 

  • Wu ZZ, Chen SR, Pan HL (2004) Differential sensitivity of N- and P/Q-type Ca2+ channel currents to a mu opioid in isolectin B4-positive and -negative dorsal root ganglion neurons. J Pharmacol Exp Ther 311:939–947

    CAS  PubMed  Google Scholar 

  • Wu ZZ, Chen SR, Pan HL (2008) Distinct inhibition of voltage-activated Ca2+ channels by delta-opioid agonists in dorsal root ganglion neurons devoid of functional T-type Ca2+ currents. Neuroscience 153:1256–1267

    CAS  PubMed  Google Scholar 

  • Yu FH, Catterall WA (2004) The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE 2004:re15

    PubMed  Google Scholar 

  • Yue X et al (2008) Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner. Eur J Pharmacol 584:272–277

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yusaf SP, Goodman J, Pinnock RD, Dixon AK, Lee K (2001) Expression of voltage-gated calcium channel subunits in rat dorsal root ganglion neurons. Neurosci Lett 311:137–141

    CAS  PubMed  Google Scholar 

  • Zachariou V, Goldstein BD (1996) Delta-opioid receptor modulation of the release of substance P-like immunoreactivity in the dorsal horn of the rat following mechanical or thermal noxious stimulation. Brain Res 736:305–314

    CAS  PubMed  Google Scholar 

  • Zaki PA et al (1996) Opioid receptor types and subtypes: the delta receptor as a model. Annu Rev Pharmacol Toxicol 36:379–401

    CAS  PubMed  Google Scholar 

  • Zamponi GW (2016) Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov 15:19–34

    CAS  PubMed  Google Scholar 

  • Zamponi GW, Bourinet E, Nelson D, Nargeot J, Snutch TP (1997) Crosstalk between G proteins and protein kinase C mediated by the calcium channel alpha1 subunit. Nature 385:442–446

    CAS  PubMed  Google Scholar 

  • Zhang X, Bao L, Arvidsson U, Elde R, Hokfelt T (1998) 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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zhu Y et al (1999) Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24:243–252

    CAS  PubMed  Google Scholar 

  • Zoga V et al (2010) KATP channel subunits in rat dorsal root ganglia: alterations by painful axotomy. Mol Pain 6:6

    PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  • Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

G.S. was supported by NIH/NIDA grant DA031777 and a Rita Allen Foundation and American Pain Society award. A.F. was supported by a Stanford Dean’s fellowship. We thank Dr. Dong Wang for providing unpublished in situ hybridization images (Fig. 1a, b), and Elizabeth Sypek and Dr. Kristen Hymel Scherrer for their helpful comments on the manuscript.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford Neurosciences Institute, Stanford University School of Medicine, Palo Alto, CA, USA

    Amaury François & Grégory Scherrer

  2. Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University School of Medicine, Palo Alto, CA, USA

    Amaury François & Grégory Scherrer

  3. Department of Neurosurgery, Stanford Neurosciences Institute, Stanford University School of Medicine, Palo Alto, CA, USA

    Amaury François & Grégory Scherrer

Authors
  1. Amaury François
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Grégory Scherrer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Grégory Scherrer .

Editor information

Editors and Affiliations

  1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    Emily M. Jutkiewicz

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

François, A., Scherrer, G. (2017). Delta Opioid Receptor Expression and Function in Primary Afferent Somatosensory Neurons. In: Jutkiewicz, E. (eds) Delta Opioid Receptor Pharmacology and Therapeutic Applications. Handbook of Experimental Pharmacology, vol 247. Springer, Cham. https://doi.org/10.1007/164_2017_58

Download citation

Publish with us

Policies and ethics

Search

Navigation