Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia

Nature Medicine

Volumn 23, Issue 2, 2017, Pages 164-173

  Corder, Gregory ^a,b   Tawfik, Vivianne L ^a,b   Wang, Dong ^a,b   Sypek, Elizabeth I ^a,b   Low, Sarah A ^a,b   Dickinson, Jasmine R ^a,b   Sotoudeh, Chaudy ^a,b   Clark, J David ^a,c   Barres, Ben A ^b   Bohlen, Christopher J ^b   Scherrer, Grégory ^a,b  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b STANFORD UNIVERSITY   (United States)

^c VA PALO ALTO HEALTH CARE SYSTEM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

17 METHYLNALTREXONE; MESSENGER RNA; MORPHINE; MU OPIATE RECEPTOR; MU OPIATE RECEPTOR ANTAGONIST; TRANSCRIPTOME; NALTREXONE; NARCOTIC ANALGESIC AGENT; OPRM PROTEIN, MOUSE; QUATERNARY AMMONIUM DERIVATIVE;

ANALGESIA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINOCICEPTION; ARTICLE; CELL ACTIVATION; CHRONIC PAIN; CONTROLLED STUDY; EXON; GENE; GENE DELETION; HISTOLOGY; IMMUNOHISTOCHEMISTRY; IMMUNOREACTIVITY; IN SITU HYBRIDIZATION; LONG TERM POTENTIATION; MICROGLIA; MORPHINE TOLERANCE; MOUSE; NONHUMAN; PAIN; PAIN RECEPTOR; PRESYNAPTIC MEMBRANE; PRIORITY JOURNAL; PROTEIN EXPRESSION; RNA SEQUENCE; SIGNAL TRANSDUCTION; SPINAL CORD; TIBIA FRACTURE; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICALLY INDUCED; CYTOLOGY; DISEASE MODEL; DRUG EFFECTS; DRUG TOLERANCE; GENETICS; HYPERALGESIA; KNOCKOUT MOUSE; METABOLISM; NOCICEPTION; POSTOPERATIVE PAIN;

ANALGESIA; ANALGESICS, OPIOID; ANIMALS; CHRONIC PAIN; DISEASE MODELS, ANIMAL; DRUG TOLERANCE; GENE DELETION; HYPERALGESIA; LONG-TERM POTENTIATION; MICE; MICE, KNOCKOUT; MICROGLIA; MORPHINE; NALTREXONE; NOCICEPTION; NOCICEPTORS; PAIN, POSTOPERATIVE; QUATERNARY AMMONIUM COMPOUNDS; RECEPTORS, OPIOID, MU; SIGNAL TRANSDUCTION; SPINAL CORD;

EID: 85009781511     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.4262     Document Type: Article

References (79)

1. Carroll, I.R., Angst, M.S. & Clark, J.D. Management of perioperative pain in patients chronically consuming opioids. Reg. Anesth. Pain Med. 29, 576-591 (2004).
2. Kalso, E., Edwards, J.E., Moore, R.A. & McQuay, H.J. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 112, 372-380 (2004).
3. Simon, L.S. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. J. Pain Palliative Care Pharmacother. 26, 197-198 (2012).
4. Volkow, N.D. & McLellan, A.T. Opioid abuse in chronic pain-misconceptions and mitigation strategies. N. Engl. J. Med. 374, 1253-1263 (2016).
5. Chu, L.F., Angst, M.S. & Clark, D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin. J. Pain 24, 479-496 (2008).
6. Angst, M.S. & Clark, J.D. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 104, 570-587 (2006).
7. Collett, B.J. Opioid tolerance: the clinical perspective. Br. J. Anaesth. 81, 58-68 (1998).
8. Matthes, H.W. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the μ-opioid-receptor gene. Nature 383, 819-823 (1996).
9. Mansour, A., Fox, C.A., Akil, H. & Watson, S.J. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 18, 22-29 (1995).
10. Ferrini, F. et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl- homeostasis. Nat. Neurosci. 16, 183-192 (2013).
11. Wang, Y. et al. Blockade of PDGFR-β activation eliminates morphine analgesic tolerance. Nat. Med. 18, 385-387 (2012).
12. Christie, M.J. Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br. J. Pharmacol. 154, 384-396 (2008).
13. Rivat, C. & Ballantyne, J. The dark side of opioids in pain management: basic science explains clinical observation. Pain Rep. 1, e570 (2016).
14. Roeckel, L.-A., Le Coz, G.-M., Gavériaux-Ruff, C. & Simonin, F. Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 338, 160-182 (2016).
15. Trang, T. et al. Pain and poppies: the good, the bad, and the ugly of opioid analgesics. J. Neurosci. 35, 13879-13888 (2015).
16. Raghavendra, V., Tanga, F.Y. & DeLeo, J.A. Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 29, 327-334 (2004).
17. Watkins, L.R., Hutchinson, M.R., Rice, K.C. & Maier, S.F. The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol. Sci. 30, 581-591 (2009).
18. Kao, S.-C. Absence of μ opioid receptor mRNA expression in astrocytes and microglia of rat spinal cord. Neuroreport 23, 378-384 (2012).
19. Hutchinson, M.R. et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav. Immun. 24, 83-95 (2010).
20. Mattioli, T.A. et al. Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence. PLoS One 9, e97361 (2014).
21. Fukagawa, H., Koyama, T., Kakuyama, M. & Fukuda, K. Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4. J. Anesth. 27, 93-97 (2013).
22. Mao, J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 100, 213-217 (2002).
23. Joseph, E.K., Reichling, D.B. & Levine, J.D. Shared mechanisms for opioid tolerance and a transition to chronic pain. J. Neurosci. 30, 4660-4666 (2010).
24. Ruscheweyh, R., Wilder-Smith, O., Drdla, R., Liu, X.-G. & Sandkühler, J. Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol. Pain 7, 20 (2011).
25. Reichling, D.B. & Levine, J.D. Critical role of nociceptor plasticity in chronic pain. Trends Neurosci. 32, 611-618 (2009).
26. Heinke, B., Gingl, E. & Sandkühler, J. Multiple targets of μ-opioid receptor-mediated presynaptic inhibition at primary afferent Aδ-and C-fibers. J. Neurosci. 31, 1313-1322 (2011).
27. Drdla, R., Gassner, M., Gingl, E. & Sandkuhler, J. Induction of synaptic long-term potentiation after opioid withdrawal. Science 325, 207-210 (2009).
28. Zhou, H.-Y.Y., Chen, S.-R.R., Chen, H. & Pan, H.-L.L. Opioid-induced long-term potentiation in the spinal cord is a presynaptic event. J. Neurosci. 30, 4460-4466 (2010).
29. Chen, S.R., Prunean, A., Pan, H.M., Welker, K.L. & Pan, H.L. Resistance to morphine analgesic tolerance in rats with deleted transient receptor potential vanilloid type 1-expressing sensory neurons. Neuroscience 145, 676-685 (2007).
30. Scherrer, G. et al. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 137, 1148-1159 (2009).
31. Usoskin, D. et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat. Neurosci. 18, 145-153 (2015).
32. Pasternak, G.W. Opioids and their receptors: are we there yet? Neuropharmacology 76Part B, 198-203 (2014).
33. Cavanaugh, D.J. et al. 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 (2011).
34. Kemp, T., Spike, R.C., Watt, C. & Todd, A.J. The μ-opioid receptor (MOR1) is mainly restricted to neurons that do not contain GABA or glycine in the superficial dorsal horn of the rat spinal cord. Neuroscience 75, 1231-1238 (1996).
35. Heinl, C., Drdla-Schutting, R., Xanthos, D.N. & Sandkühler, J. Distinct mechanisms underlying pronociceptive effects of opioids. J. Neurosci. 31, 16748-16756 (2011).
36. Zhao, Y.L., Chen, S.R., Chen, H. & Pan, H.L. Chronic opioid potentiates presynaptic but impairs postsynaptic N-methyl-D-aspartic acid receptor activity in spinal cords: implications for opioid hyperalgesia and tolerance. J. Biol. Chem. 287, 25073-25085 (2012).
37. Russell, J., Bass, P., Goldberg, L.I., Schuster, C.R. & Merz, H. Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists. Eur. J. Pharmacol. 78, 255-261 (1982).
38. Stiene-Martin, A., Zhou, R. & Hauser, K.F. Regional, developmental and cell-cycle-dependent differences in mu, delta, and kappa-opioid receptor expression among cultured mouse astrocytes. Glia 22, 249-259 (1998).
39. Turchan-Cholewo, J. et al. Cell-specific actions of HIV-Tat and morphine on opioid receptor expression in glia. J. Neurosci. Res. 86, 2100-2110 (2008).
40. Horvath, R.J., Romero-Sandoval, E.A. & De Leo, J.A. Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and μ opioid receptor protein expression while enhancing perivascular microglial ED2. Pain 150, 401-413 (2010).
41. Caldeira, C. et al. Microglia change from a reactive to an age-like phenotype with the time in culture. Front. Cell. Neurosci. 8, 152 (2014).
42. Foo, L.C. et al. Development of a method for the purification and culture of rodent astrocytes. Neuron 71, 799-811 (2011).
43. Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929-11947 (2014).
44. Zhang, Y. et al. Essential role of toll-like receptor 2 in morphine-induced microglia activation in mice. Neurosci. Lett. 489, 43-47 (2011).
45. Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94-101 (2016).
46. Kronschläger, M.T. et al. Gliogenic LTP spreads widely in nociceptive pathways. Science 354, 1144-1148 (2016).
47. He, S.Q. et al. Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats. Pain 154, 2477-2486 (2013).
48. Chen, L.H., Hedegaard, H. & Warner, M. Drug-poisoning deaths involving opioid analgesics: United States, 1999-2011. NCHS Data Brief 166, 1-8 (2014).
49. Thomas, J. et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N. Engl. J. Med. 358, 2332-2343 (2008).
50. Yu, C.S. et al. Safety and efficacy of methylnaltrexone in shortening the duration of postoperative ileus following segmental colectomy: results of two randomized, placebo-controlled phase 3 trials. Dis. Colon Rectum 54, 570-578 (2011).
51. Webster, L.R. et al. Analysis of opioid-mediated analgesia in Phase III studies of methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain. J. Pain Res. 8, 771-780 (2015).
52. Poelaert, J. et al. Treatment with prolonged-release oxycodone/naloxone improves pain relief and opioid-induced constipation compared with prolonged-release oxycodone in patients with chronic severe pain and laxative-refractory constipation. Clin. Ther. 37, 784-792 (2015).
53. Jagla, C., Martus, P. & Stein, C. Peripheral opioid receptor blockade increases postoperative morphine demands-a randomized, double-blind, placebo-controlled trial. Pain 155, 2056-2062 (2014).
54. Zacny, J.P., Wroblewski, K. & Coalson, D.W. Methylnaltrexone: its pharmacological effects alone and effects on morphine in healthy volunteers. Psychopharmacology (Berl.) 232, 63-73 (2015).
55. Rosow, C.E. et al. Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone. Clin. Pharmacol. Ther. 82, 48-53 (2007).
56. Stein, C. et al. Peripheral mechanisms of pain and analgesia. Brain Res. Rev. 60, 90-113 (2009).
57. Corder, G. et al. Constitutive μ-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science 341, 1394-1399 (2013).
58. Weibel, R. et al. μ opioid receptors on primary afferent nav1.8 neurons contribute to opiate-induced analgesia: insight from conditional knockout mice. PLoS One 8, e74706 (2013).
59. Sorge, R.E. et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat. Methods 11, 629-632 (2014).
60. Mogil, J.S. Animal models of pain: progress and challenges. Nat. Rev. Neurosci. 10, 283-294 (2009).
61. Manglik, A. et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185-190 (2016).
62. Woolf, C.J. Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat. Pain 18, 325-343 (1984).
63. Rescorla, R.A. Pavlovian conditioned fear in Sidman avoidance learning. J. Comp. Physiol. Psychol. 65, 55-60 (1968).
64. Blanchard, R.J. & Blanchard, D.C. Passive and active reactions to fear-eliciting stimuli. J. Comp. Physiol. Psychol. 68, 129-135 (1969).
65. Bolles, R.C. Species-specific defense reactions and avoidance learning. Psychol. Rev. 77, 32-48 (1970).
66. Bolles, R.C. & Fanselow, M.S. A perceptual-defensive-recuperative model of fear and pain. Behav. Brain Sci. 3, 291-301 (1980).
67. Fanselow, M.S. The postshock activity burst. Anim. Learn. Behav. 10, 448-454 (1982).
68. Darwin, C. The Expression of The Emotions in Man and Animals (Albemarle, 1872).
69. Chaplan, S.R., Bach, F.W., Pogrel, J.W., Chung, J.M. & Yaksh, T.L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55-63 (1994).
70. Solway, B., Bose, S.C., Corder, G., Donahue, R.R. & Taylor, B.K. Tonic inhibition of chronic pain by neuropeptide Y. Proc. Natl. Acad. Sci. USA 108, 7224-7229 (2011).
71. Madisen, L. et al. A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat. Neurosci. 15, 793-802 (2012).
72. Bardoni, R. et al. Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn. Neuron 81, 1312-1327 (2014).
73. Picelli, S. et al. Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat. Methods 10, 1096-1098 (2013).
74. Kim, D., Langmead, B. & Salzberg, S.L. HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357-360 (2015).
75. Quinlan, A.R. & Hall, I.M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841-842 (2010).
76. Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511-515 (2010).
77. Bennett, G.J. & Xie, Y.K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87-107 (1988).
78. Wall, P.D. et al. Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 7, 103-111 (1979).
79. Terrando, N. et al. Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Mol. Med. 20, 667-675 (2015).