The Light Touch of Delta Opioid Receptors
Authors: Wendy Imlach, Macdonald J. Christie
Journal: Neuron (2014)

Expression of δ-opioid receptors in sensory neurons is controversial. In this issue of Neuron, Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar present evidence that DOPrs are expressed on mechanosensory neurons involved in detecting nonnoxious touch but are very sparse in μ-opioid receptor-rich nociceptive neurons. Expression of δ-opioid receptors in sensory neurons is controversial. In this issue of Neuron, Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar present evidence that DOPrs are expressed on mechanosensory neurons involved in detecting nonnoxious touch but are very sparse in μ-opioid receptor-rich nociceptive neurons. The analgesic actions of μ-opioid receptor (MOPr) drugs on thermal and mechanical pain-sensing primary afferent neurons are well known. The selective expression of MOPr in small, unmyelinated nociceptive neurons (Scherrer et al., 2009Scherrer G. Imamachi N. Cao Y.Q. Contet C. Mennicken F. O’Donnell D. Kieffer B.L. Basbaum A.I. Cell. 2009; 137: 1148-1159Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar, Heinke et al., 2011Heinke B. Gingl E. Sandkühler J. J. Neurosci. 2011; 31: 1313-1322Crossref PubMed Scopus (106) Google Scholar) nicely explains why MOPr-selective opioid drugs relieve pain with little disruption of other somatosensory modalities. By contrast, the location and function of δ-opioid receptors (DOPr) in sensory systems are controversial. The controversy centers on the extent to which DOPr is coexpressed with MOPr in thermal nociceptors (Guan et al., 2005Guan J.S. Xu Z.Z. Gao H. He S.Q. Ma G.Q. Sun T. Wang L.H. Zhang Z.N. Lena I. Kitchen I. et al.Cell. 2005; 122: 619-631Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, Wang et al., 2010Wang H.B. Zhao B. Zhong Y.Q. Li K.C. Li Z.Y. Wang Q. Lu Y.J. Zhang Z.N. He S.Q. Zheng H.C. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 13117-13122Crossref PubMed Scopus (174) Google Scholar, He et al., 2011He S.Q. Zhang Z.N. Guan J.S. Liu H.R. Zhao B. Wang H.B. Li Q. Yang H. Luo J. Li Z.Y. et al.Neuron. 2011; 69: 120-131Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar) versus selective expression in mechanosensory neurons. Resolving this is crucial for understanding the role of endogenous opioid systems in pain and other sensory processes, as well as for potential therapeutic development of novel opioid drugs that interact selectively with DOPr or hetero-oligomers between MOPr and DOPr (Fujita et al., 2014Fujita W. Gomes I. Devi L.A. Br. J. Pharmacoldol. 2014; (Published online February 26, 2014)https://doi.org/10.1111/bph.12663Crossref Scopus (73) Google Scholar). In this issue of Neuron, Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar present convincing anatomical and physiological evidence that DOPr is expressed predominantly by neurons involved in cutaneous nonnoxious mechanosensation. Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar have greatly strengthened the previous conclusion (Scherrer et al., 2009Scherrer G. Imamachi N. Cao Y.Q. Contet C. Mennicken F. O’Donnell D. Kieffer B.L. Basbaum A.I. Cell. 2009; 137: 1148-1159Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar) that DOPr is rarely expressed by the MOPr-rich, small C fiber neurons that are likely to be nociceptors. They used a transgenic DOPr-eGFP mouse combined with extensive immunohistochemical classification of sensory types in dorsal root ganglion (DRG) and skin, a functional skin-nerve preparation, and DRG cellular and spinal synaptic physiology to provide compelling evidence that DOPrs are expressed by defined classes of low-threshold mechanoreceptors (LTMRs). The conclusions are clear and finding DOPr on a range of mechanosensory neurons is not surprising because it was previously predicted from the distribution of DOPr mRNA in NF200 DRG neurons in rodents and humans (Mennicken et al., 2003Mennicken F. Zhang J. Hoffert C. Ahmad S. Beaudet A. O’Donnell D. J. Comp. Neurol. 2003; 465: 349-360Crossref PubMed Scopus (63) Google Scholar). Moreover, Minami et al., 1995Minami M. Maekawa K. Yabuuchi K. Satoh M. Brain Res. Mol. Brain Res. 1995; 30: 203-210Crossref PubMed Scopus (135) Google Scholar found that only a small proportion (5%) of small C fiber substance P (SP)-expressing neurons contained DOPr mRNA by double in situ hybridization. However, the new findings place the expression of DOPr firmly in the domain of light touch (Figure 1). There is already extensive evidence that noxious heat and mechanical stimuli are processed by distinct populations of primary afferent fibers (Cavanaugh et al., 2009Cavanaugh D.J. Lee H. Lo L. Shields S.D. Zylka M.J. Basbaum A.I. Anderson D.J. Proc. Natl. Acad. Sci. USA. 2009; 106: 9075-9080Crossref PubMed Scopus (498) Google Scholar, Abrahamsen et al., 2008Abrahamsen B. Zhao J. Asante C.O. Cendan C.M. Marsh S. Martinez-Barbera J.P. Nassar M.A. Dickenson A.H. Wood J.N. Science. 2008; 321: 702-705Crossref PubMed Scopus (355) Google Scholar, Scherrer et al., 2009Scherrer G. Imamachi N. Cao Y.Q. Contet C. Mennicken F. O’Donnell D. Kieffer B.L. Basbaum A.I. Cell. 2009; 137: 1148-1159Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar), the “labeled line” hypothesis. Lightly myelinated Aδ fibers and nonpeptidergic unmyelinated C fibers transmit noxious mechanical stimuli, while peptidergic C fibers that express SP are activated by noxious heat. Tuning of primary afferent neurons also depends on receptor and ion channel expression, their association with specialized structures in the skin that detect stimuli, and integration in the dorsal horn of the spinal cord (Abraira and Ginty, 2013Abraira V.E. Ginty D.D. Neuron. 2013; 79: 618-639Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar). Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar add distinct expression of DOPr and MOPr in light mechanical versus thermal nociceptive lines to this. It is well established that DOPr agonists inhibit mechanical nociception (Scherrer et al., 2009Scherrer G. Imamachi N. Cao Y.Q. Contet C. Mennicken F. O’Donnell D. Kieffer B.L. Basbaum A.I. Cell. 2009; 137: 1148-1159Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar) and Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar make a good case for the potential of DOPr agonists to treat mechanical allodynia in chronic pain states. However, the extensive expression of DOPr in LTMRs involved in light touch suggests that widespread somatosensory side effects could also be problematic with DOPr agonists. The findings of Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar are at odds with other prominent studies suggesting that DOPr is expressed in peptidergic neurons involved in thermal nociception (Guan et al., 2005Guan J.S. Xu Z.Z. Gao H. He S.Q. Ma G.Q. Sun T. Wang L.H. Zhang Z.N. Lena I. Kitchen I. et al.Cell. 2005; 122: 619-631Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, Wang et al., 2010Wang H.B. Zhao B. Zhong Y.Q. Li K.C. Li Z.Y. Wang Q. Lu Y.J. Zhang Z.N. He S.Q. Zheng H.C. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 13117-13122Crossref PubMed Scopus (174) Google Scholar, He et al., 2011He S.Q. Zhang Z.N. Guan J.S. Liu H.R. Zhao B. Wang H.B. Li Q. Yang H. Luo J. Li Z.Y. et al.Neuron. 2011; 69: 120-131Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). Scherrer et al., 2009Scherrer G. Imamachi N. Cao Y.Q. Contet C. Mennicken F. O’Donnell D. Kieffer B.L. Basbaum A.I. Cell. 2009; 137: 1148-1159Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar found DOPr-eGFP expression in SP neurons to be very rare and many of the previous findings of Guan et al., 2005Guan J.S. Xu Z.Z. Gao H. He S.Q. Ma G.Q. Sun T. Wang L.H. Zhang Z.N. Lena I. Kitchen I. et al.Cell. 2005; 122: 619-631Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar were countered. However, Wang et al., 2010Wang H.B. Zhao B. Zhong Y.Q. Li K.C. Li Z.Y. Wang Q. Lu Y.J. Zhang Z.N. He S.Q. Zheng H.C. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 13117-13122Crossref PubMed Scopus (174) Google Scholar reported that DOPr is expressed in about 70% of small neurons, 30% of which are SP neurons using in situ hybridization and single-cell PCR and showed coexpression of DOPr and MOPr in a large proportion of DRG neurons using inhibition of calcium channel currents in patch-clamp recordings. Other reports from the same group also provide pharmacological evidence that DOPr is expressed in small DRG neurons (Guan et al., 2005Guan J.S. Xu Z.Z. Gao H. He S.Q. Ma G.Q. Sun T. Wang L.H. Zhang Z.N. Lena I. Kitchen I. et al.Cell. 2005; 122: 619-631Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, He et al., 2011He S.Q. Zhang Z.N. Guan J.S. Liu H.R. Zhao B. Wang H.B. Li Q. Yang H. Luo J. Li Z.Y. et al.Neuron. 2011; 69: 120-131Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). Poor specificity of DOPr antibodies might explain some of the discrepancies. Moreover, the use of very high, nonselective concentrations of DOPr agonists by Wang et al., 2010Wang H.B. Zhao B. Zhong Y.Q. Li K.C. Li Z.Y. Wang Q. Lu Y.J. Zhang Z.N. He S.Q. Zheng H.C. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 13117-13122Crossref PubMed Scopus (174) Google Scholar and possibly nonselective concentrations of antagonists is questionable. Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar rightly tested 500 nM deltorphin II, a high but most likely selective concentration, and found only 1 of 29 neurons responded to both MOPr and DOPr agonists (including wild-type mice), rather than the 10 μM SNC80 used by Wang et al., 2010Wang H.B. Zhao B. Zhong Y.Q. Li K.C. Li Z.Y. Wang Q. Lu Y.J. Zhang Z.N. He S.Q. Zheng H.C. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 13117-13122Crossref PubMed Scopus (174) Google Scholar, which must be considered nonselective. Other studies claiming direct DOPr effects on small DRG neurons have used almost completely nonselective antagonists such as DADLE, so they cannot be considered seriously. To our knowledge, no other well-controlled pharmacological studies have reported direct physiological effects of DOPr agonists in small, presumed nociceptive DRG neurons or in the superficial laminae of the spinal dorsal horn. Poor pharmacological selectivity and failure to use appropriate antagonist controls for DOPr agonists in vivo could also explain many studies that have claimed involvement of DOPr in thermal nociception. This problem is clearly evidenced by the persistence of analgesia induced by a range of DOPr agonists in Oprd1 knockout mice (Kieffer and Gavériaux-Ruff, 2002Kieffer B.L. Gavériaux-Ruff C. Prog. Neurobiol. 2002; 66: 285-306Crossref PubMed Scopus (508) Google Scholar). The discrepancies between Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and other methods used by Wang et al., 2010Wang H.B. Zhao B. Zhong Y.Q. Li K.C. Li Z.Y. Wang Q. Lu Y.J. Zhang Z.N. He S.Q. Zheng H.C. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 13117-13122Crossref PubMed Scopus (174) Google Scholar are more difficult to explain away. Both groups used in situ hybridization with contradictory results. One set of results must be wrong. The discrepancy could be resolved by testing the two methods in question in knockout animals. Until the specificity of the molecular methods is established, it will remain uncertain which research group is right but on balance the high levels of physiological evidence presented by Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar are more convincing. An alternative interpretation of the findings of Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and Scherrer et al., 2009Scherrer G. Imamachi N. Cao Y.Q. Contet C. Mennicken F. O’Donnell D. Kieffer B.L. Basbaum A.I. Cell. 2009; 137: 1148-1159Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar is that the DOPr-eGFGP is not found in many peptidergic neurons because the attachment of eGFP near the C terminus of the receptor disrupts the trafficking and/or degradation of DOPr in SP neurons (Wang et al., 2010Wang H.B. Zhao B. Zhong Y.Q. Li K.C. Li Z.Y. Wang Q. Lu Y.J. Zhang Z.N. He S.Q. Zheng H.C. et al.Proc. Natl. Acad. Sci. USA. 2010; 107: 13117-13122Crossref PubMed Scopus (174) Google Scholar). These authors presented evidence that this is the case by showing disrupted trafficking of a DOPR-eGFP construct when transfected into small DRG neurons. However, Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar have nicely answered this criticism by showing an identical distribution of Oprd1 mRNA using in situ hybridization and electrophysiology in wild-type mice. It remains possible that the DOPr-eGFP transgenic construct is not trafficked in the same way as the native DOPr, but this is not important for the findings reported by Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar. It is important to establish the colocalization of MOPr and DOPr beyond doubt in neurons in pain pathways because there is growing evidence that these receptors can exist as hetero-oligomers and there are novel heteromer-selective opioid therapeutics currently being developed (Fujita et al., 2014Fujita W. Gomes I. Devi L.A. Br. J. Pharmacoldol. 2014; (Published online February 26, 2014)https://doi.org/10.1111/bph.12663Crossref Scopus (73) Google Scholar). Of course, the two receptors must be coexpressed to potentially oligomerize and the convincing evidence of Bardoni et al., 2014Bardoni R. Tawfik V.L. Wang D. François A. Solorzano C. Shuster S.A. Choudhury P. Betelli C. Cassidy C. Smith K. et al.Neuron. 2014; 81 (this issue): 1312-1327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar suggests that MOPr-DOPr hetero-oligomers occur rarely, if at all, in nociceptive sensory neurons. Indeed, recent evidence on colocalization of DOPr-eGFP and MOPr-mcherry throughout the CNS suggests that colocalization is very uncommon but does occur in some pain-related areas of the brain (Erbs et al., 2014Erbs E. Faget L. Scherrer G. Matifas A. Filliol D. Vonesch J.-L. Koch M. Kessler P. Hentsch D. Birling M.-C. et al.Brain Struct. Funct. 2014; https://doi.org/10.1007/s00429-014-0717-9Crossref PubMed Scopus (164) Google Scholar). The biological significance of segregation of DOPr and MOPr in sensory afferents is unknown. Under some physiological and pathological conditions, both types of sensory nerves are likely to be bathed in endogenous opioids that act on each receptor with similar affinities (Williams et al., 2001Williams J.T. Christie M.J. Manzoni O. Physiol. Rev. 2001; 81: 299-343Crossref PubMed Scopus (719) Google Scholar). DOPr and MOPr produce similar intracellular signals but upon activation DOPr is trafficked to a lysosomal degradation pathway, while MOPr is recycled. Perhaps this property produces transient suppression of light mechanical sensation by DOPr because the receptor is degraded versus prolonged inhibition of nociception by MOPr during sustained episodes of endogenous opioid release. Delta Opioid Receptors Presynaptically Regulate Cutaneous Mechanosensory Neuron Input to the Spinal Cord Dorsal HornBardoni et al.NeuronFebruary 27, 2014In BriefBardoni et al. report that the opioid system not only controls pain but broadly regulates cutaneous mechanosensation, including touch. They demonstrate that the delta opioid receptor inhibits voltage-gated calcium channels to depress myelinated mechanosensory neuron input to the spinal cord. Full-Text PDF Open Archive