Analgesic synergy between opioid and α2-adrenoceptors

British Journal of Pharmacology

Volumn 172, Issue 2, 2015, Pages 388-402

  Chabot Dore A J ^a,b   Schuster, D J ^b   Stone, L S ^a,b,c,d   Wilcox, G L ^b,d  

^a MCGILL UNIVERSITY   (Canada)

^b MCGILL UNIVERSITY   (Canada)

^c MCGILL UNIVERSITY   (Canada)

^d UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

analgesia; spinal; synergy; 2 adrenoceptors; opioid receptor; opioid receptor

Indexed keywords

2 (2,6 DIETHYLANILINO) 2 IMIDAZOLINE; 4 [ALPHA (4 ALLYL 2,5 DIMETHYL 1 PIPERAZINYL) 3 METHOXYBENZYL] N,N DIETHYLBENZAMIDE; ALPHA 2 ADRENERGIC RECEPTOR; ALPHA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; ALPHA 2A ADRENERGIC RECEPTOR; ALPHA 2A ADRENERGIC RECEPTOR AGONIST; ALPHA 2C ADRENERGIC RECEPTOR; BRIMONIDINE; CLONIDINE; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; DELTA OPIATE RECEPTOR; DELTA OPIATE RECEPTOR AGONIST; ENDORPHIN; ENKEPHALIN[2 DEXTRO ALANINE 4 METHYLPHENYLALANINE 5 GLYCINE]; ENKEPHALIN[2,5 DEXTRO PENICILLAMINE]; FENTANYL; MORPHINE; MOXONIDINE; MU OPIATE RECEPTOR; MU OPIATE RECEPTOR AGONIST; NORADRENALIN; OPIATE AGONIST; OPIATE DERIVATIVE; OPIATE RECEPTOR; PETHIDINE; PROTEIN KINASE C EPSILON; UNCLASSIFIED DRUG; UNINDEXED DRUG; VOLTAGE GATED CALCIUM CHANNEL; [2 DEXTRO ALANINE]DELTORPHIN; ALPHA ADRENERGIC RECEPTOR STIMULATING AGENT; NARCOTIC ANALGESIC AGENT;

ABSENCE OF SIDE EFFECTS; ADJUVANT THERAPY; ANALGESIA; ANALGESIC ACTIVITY; CELLULAR DISTRIBUTION; CHRONIC PAIN; CONSTIPATION; DEPRESSED BLOOD PRESSURE; DRUG ANTAGONISM; DRUG CLEARANCE; DRUG DEPENDENCE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG MEGADOSE; DRUG POTENCY; DRUG POTENTIATION; DRUG TARGETING; DRUG TOLERANCE; ENZYME ACTIVATION; HUMAN; HYPOTENSION; INFLAMMATORY PAIN; LEG PAIN; LONG TERM CARE; LOW BACK PAIN; NEUROPATHIC PAIN; NONHUMAN; OLIGOMERIZATION; PAIN; PHARMACODYNAMICS; PROTEIN CONFORMATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; RESPIRATION DEPRESSION; REVIEW; SEDATION; SIGNAL TRANSDUCTION; SPINAL CORD; UNSPECIFIED SIDE EFFECT; VASOCONSTRICTION; ANIMAL; METABOLISM;

ADRENERGIC ALPHA-AGONISTS; ANALGESIA; ANALGESICS, OPIOID; ANIMALS; DRUG SYNERGISM; HUMANS; RECEPTORS, ADRENERGIC, ALPHA-2; RECEPTORS, OPIOID;

EID: 84920136258     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12695     Document Type: Review

References (126)

1. Ackerman LL, Follett KA, Rosenquist RW, (2003). Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations. J Pain Symptom Manage 26: 668-677.
2. Aicher SA, Punnoose A, Goldberg A, (2000). Mu-opioid receptors often colocalize with the substance P receptor (NK1) in the trigeminal dorsal horn. J Neurosci 20: 4345-4354.
3. Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, et al. (2013a). The Concise Guide to PHARMACOLOGY 2013/14: G Protein-Coupled Receptors. Br J Pharmacol 170: 1459-1581.
4. Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Catterall WA, et al. (2013b). The Concise Guide to PHARMACOLOGY 2013/14: Ion Channels. Br J Pharmacol 170: 1607-1651.
5. Arnér S, Meyerson BA, (1988). Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 33: 11-23.
6. Arvidsson U, Riedl M, Chakrabarti S, Lee JH, Nakano AH, Dado RJ, et al. (1995). Distribution and targeting of a mu-opioid receptor (MOR1) in brain and spinal cord. The J Neurosci 15 (5 Pt 1): 3328-3341.
7. Asada Y, Lee TJ, (1992). Alpha 2-adrenoceptors mediate norepinephrine constriction of porcine pial veins. Am J Physiol 263 (6 Pt 2): H1907-H1910.
8. Bao L, Jin S-X, Zhang C, Wang L-H, Xu Z-Z, Zhang F-X, et al. (2003). Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron 37: 121-133.
9. Beaudry H, Proteau-Gagné A, Li S, Dory Y, Chavkin C, Gendron L, (2009). Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents. Neuroscience 161: 381-391.
10. Beaudry H, Dubois D, Gendron L, (2011). Activation of spinal μ- and δ-opioid receptors potently inhibits substance P release induced by peripheral noxious stimuli. J Neurosci 31: 13068-13077.
11. Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, et al. (1994). International union of pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46: 121-136.
12. Cahill CM, McClellan KA, Morinville A, Hoffert C, Hubatsch D, O'Donnell D, et al. (2001a). 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.
13. Cahill CM, Morinville A, Lee MC, Vincent JP, Collier B, Beaudet A, (2001b). Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances delta-mediated antinociception. J Neurosci 21: 7598-7607.
14. Cahill CM, Morinville A, Hoffert C, O'Donnell D, Beaudet A, (2003). Up-regulation and trafficking of delta opioid receptor in a model of chronic inflammation: implications for pain control. Pain 101: 199-208.
15. Cesare P, Dekker LV, Sardini A, Parker PJ, McNaughton PA, (1999). Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Neuron 23: 617-624.
16. Chabot-Doré A-J, Millecamps M, Stone LS, (2013). The delta-opioid receptor is sufficient, but not necessary, for spinal opioid-adrenergic synergy. J Pharmacol Exp Ther 347: 773-780.
17. Cheng PY, Liu-Chen LY, Pickel VM, (1997). Dual ultrastructural immunocytochemical labeling of mu and delta opioid receptors in the superficial layers of the rat cervical spinal cord. Brain Res 778: 367-380.
18. Chou WH, Wang D, McMahon T, Qi ZH, Song M, Zhang C, et al. (2010). GABAA receptor trafficking is regulated by protein kinase C (epsilon) and the N-ethylmaleimide-sensitive factor. J Neurosci 30: 13955-13965.
19. Chu J, Zheng H, Loh HH, Law P-Y, (2008). Morphine-induced mu-opioid receptor rapid desensitization is independent of receptor phosphorylation and beta-arrestins. Cell Signal 20: 1616-1624.
20. Codd EE, Carson JR, Colburn RW, Stone DJ, Van Besien CR, Zhang S-P, et al. (2009). JNJ-20788560 [9-(8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide], a selective delta opioid receptor agonist, is a potent and efficacious antihyperalgesic agent that does not produce respiratory depression, pharmacologic tolerance, or physical dependence. J Pharmacol Exp Ther 329: 241-251.
21. Coombs DW, Saunders RL, Fratkin JD, Jensen LE, Murphy CA, (1986). Continuous intrathecal hydromorphone and clonidine for intractable cancer pain. J Neurosurg 64: 890-894.
22. Costantino CM, Gomes I, Stockton SD, Lim MP, Devi LA, (2012). Opioid receptor heteromers in analgesia. Expert Rev Mol Med 14: 1-15.
23. Csukai M, Chen CH, De Matteis MA, Mochly-Rosen D, (1997). The coatomer protein beta'-COP, a selective binding protein (RACK) for protein kinase C epsilon. J Biol Chem 272: 29200-29206.
24. Dado RJ, Law PY, Loh HH, Elde R, (1993). Immunofluorescent identification of a delta (delta)-opioid receptor on primary afferent nerve terminals. Neuroreport 5: 341-344.
25. Drasner K, Fields HL, (1988). Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in the rat. Pain 32: 309-312.
26. Duflo F, Li X, Bantel C, Pancaro C, Vincler M, Eisenach JC, (2002). Peripheral nerve injury alters the alpha2 adrenoceptor subtype activated by clonidine for analgesia. Anesthesiology 97: 636-641.
27. Eisenach JC, D'Angelo R, Taylor C, Hood DD, (1994). An isobolographic study of epidural clonidine and fentanyl after caesarean section. Anesth Analg 79: 285-290.
28. Fairbanks CA, Wilcox GL, (1999). Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine. J Pharmacol Exp Ther 288: 1107-1116.
29. Fairbanks CA, Nguyen HO, Grocholski BM, Wilcox GL, (2000a). Moxonidine, a selective imidazoline-alpha2-adrenergic receptor agonist, produces spinal synergistic antihyperalgesia with morphine in nerve-injured mice. Anesthesiology 93: 765-773.
30. Fairbanks CA, Posthumus IJ, Kitto KF, Stone LS, Wilcox GL, (2000b). Moxonidine, a selective imidazoline/alpha(2) adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice. Pain 84: 13-20.
31. Fairbanks CA, Stone LS, Kitto KF, Nguyen HO, Posthumus IJ, Wilcox GL, (2002). Alpha(2C)-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J Pharmacol Exp Ther 300: 282-290.
32. Förster JG, Rosenberg PH, (2004). Small dose of clonidine mixed with low-dose ropivacaine and fentanyl for epidural analgesia after total knee arthroplasty. Br J Anaesth 93: 670-677.
33. Gendron L, Lucido AL, Mennicken F, O'Donnell D, Vincent J-P, Stroh T, 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.
34. Gessner P, (1988). A straightforward method for the study of drug interactions: an isobolographic analysis primer. Int J Toxicol 7: 987-1012.
35. Gilsbach R, Röser C, Beetz N, Brede M, Hadamek K, Haubold M, et al. (2009). Genetic dissection of alpha2-adrenoceptor functions in adrenergic versus nonadrenergic cells. Mol Pharmacol 75: 1160-1170.
36. 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.
37. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA, (2004). A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci U S A 101: 5135-5139.
38. Gomes I, Fujita W, Gupta A, Saldanha SA, Negri A, Pinello CE, et al. (2013). Identification of a mu-delta opioid receptor heteromer-biased agonist with antinociceptive activity. Proc Natl Acad Sci U S A 110: 12072-12077.
39. Gregoretti C, Moglia B, Pelosi P, Navalesi P, (2009). Clonidine in perioperative medicine and intensive care unit: more than an anti-hypertensive drug. Curr Drug Targets 10: 799-814.
40. Guo X-H, Fairbanks CA, Stone LS, Loh HH, (2003). DPDPE-UK14,304 synergy is retained in mu opioid receptor knockout mice. Pain 104: 209-217.
41. Gupta A, Mulder J, Gomes I, Rozenfeld R, Bushlin I, Ong E, et al. (2010). Increased abundance of opioid receptor heteromers after chronic morphine administration. Sci Signal 3: ra54-ra54.
42. Hao S, Takahata O, Iwasaki H, (2000). Intrathecal endomorphin-1 produces antinociceptive activities modulated by alpha 2-adrenoceptors in the rat tail flick, tail pressure and formalin tests. Life Sci 66: PL195-PL204.
43. He S-Q, Zhang Z-N, Guan J-S, Liu H-R, Zhao B, Wang H-B, et al. (2011). Facilitation of μ-opioid receptor activity by preventing δ-opioid receptor-mediated codegradation. Neuron 69: 120-131.
44. Holdridge SV, Cahill CM, (2007). Spinal administration of a delta opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Eur J Pain 11: 685-693.
45. Hylden JL, Wilcox GL, (1980). Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67: 313-316.
46. Hylden JL, Wilcox GL, (1982). Intrathecal opioids block a spinal action of substance P in mice: functional importance of both mu- and delta-receptors. Eur J Pharmacol 86: 95-98.
47. Hylden JL, Wilcox GL, (1983). Pharmacological characterization of substance P-induced nociception in mice: modulation by opioid and noradrenergic agonists at the spinal level. J Pharmacol Exp Ther 226: 398-404.
48. Iida H, Ohata H, Iida M, Watanabe Y, Dohi S, (1999). Direct effects of alpha1- and alpha2-adrenergic agonists on spinal and cerebral pial vessels in dogs. Anesthesiology 91: 479-485.
49. Johnson EA, Oldfield S, Braksator E, Gonzalez-Cuello A, Couch D, Hall KJ, et al. (2006). Agonist-selective mechanisms of mu-opioid receptor desensitization in human embryonic kidney 293 cells. Mol Pharmacol 70: 676-685.
50. Jordan BA, Gomes I, Rios C, Filipovska J, Devi LA, (2003). Functional interactions between mu opioid and alpha 2A-adrenergic receptors. Mol Pharmacol 64: 1317-1324.
51. Joseph EK, Bogen O, Alessandri-Haber N, Levine JD, (2007). PLC-beta 3 signals upstream of PKC epsilon in acute and chronic inflammatory hyperalgesia. Pain 132: 67-73.
52. Kawasaki Y, Kumamoto E, Furue H, Yoshimura M, (2003). Alpha 2 adrenoceptor-mediated presynaptic inhibition of primary afferent glutamatergic transmission in rat substantia gelatinosa neurons. Anesthesiology 98: 682-689.
53. Kingery WS, Guo TZ, Davies MF, Limbird L, Maze M, (2000). The alpha(2A) adrenoceptor and the sympathetic postganglionic neuron contribute to the development of neuropathic heat hyperalgesia in mice. Pain 85: 345-358.
54. Lakhlani PP, MacMillan LB, Guo TZ, McCool BA, Lovinger DM, Maze M, et al. (1997). Substitution of a mutant alpha2a-adrenergic receptor via 'hit and run' gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc Natl Acad Sci U S A 94: 9950-9955.
55. Lena P, Balarac N, Arnulf JJ, Teboul J, Bonnet F, (2003). Intrathecal morphine and clonidine for coronary artery bypass grafting. Br J Anaesth 90: 300-303.
56. Li X, Eisenach JC, (2001). alpha2A-adrenoceptor stimulation reduces capsaicin-induced glutamate release from spinal cord synaptosomes. J Pharmacol Exp Ther 299: 939-944.
57. Li X, Zhao Z, Pan HL, Eisenach JC, Paqueron X, (2000). Norepinephrine release from spinal synaptosomes: auto-alpha2 -adrenergic receptor modulation. Anesthesiology 93: 164-172.
58. Loomis CW, Milne B, Cervenko FW, (1988). A study of the interaction between clonidine and morphine on analgesia and blood pressure during continuous intrathecal infusion in the rat. Neuropharmacology 27: 191-199.
59. Loewe S, (1953). The problem of synergism and antagonism of combined drugs. Arzneimittel-Forschung 3: 285-290.
60. MacMillan LB, Hein L, Smith MS, Piascik MT, Limbird LE, (1996). Central hypotensive effects of the alpha2a-adrenergic receptor subtype. Science 273: 801-803.
61. Malmberg AB, Hedley LR, Jasper JR, Hunter JC, Basbaum AI, (2001). Contribution of alpha(2) receptor subtypes to nerve injury-induced pain and its regulation by dexmedetomidine. Br J Pharmacol 132: 1827-1836.
62. Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, et al. (1996). Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383: 819-823.
63. Mika J, Przewłocki R, Przewłocka B, (2001). The role of delta-opioid receptor subtypes in neuropathic pain. Eur J Pharmacol 415: 31-37.
64. Monasky MS, Zinsmeister AR, Stevens CW, Yaksh TL, (1990). Interaction of intrathecal morphine and ST-91 on antinociception in the rat: dose-response analysis, antagonism and clearance. J Pharmacol Exp Ther 254: 383-392.
65. Morinville A, Cahill CM, Esdaile MJ, Aibak H, Collier B, Kieffer BL, et al. (2003). Regulation of delta-opioid receptor trafficking via mu-opioid receptor stimulation: evidence from mu-opioid receptor knock-out mice. J Neurosci 23: 4888-4898.
66. Nagasaka H, Yaksh TL, (1990). Pharmacology of intrathecal adrenergic agonists: cardiovascular and nociceptive reflexes in halothane-anesthetized rats. Anesthesiology 73: 1198-1207.
67. Newton PM, Messing RO, (2010). The substrates and binding partners of protein kinase C epsilon. Biochem J 427: 189-196.
68. Nozaki C, Le Bourdonnec B, Reiss D, Windh RT, Little PJ, Dolle RE, et al. (2012). δ-Opioid mechanisms for ADL5747 and ADL5859 effects in mice: analgesia, locomotion, and receptor internalization. J Pharmacol Exp Ther 342: 799-807.
69. Olave MJ, Maxwell DJ, (2002). An investigation of neurones that possess the alpha 2C-adrenergic receptor in the rat dorsal horn. Neuroscience 115: 31-40.
70. Olave MJ, Maxwell DJ, (2003). Neurokinin-1 projection cells in the rat dorsal horn receive synaptic contacts from axons that possess alpha2C-adrenergic receptors. J Neurosci 23: 6837-6846.
71. Ossipov MH, Harris S, Lloyd P, Messineo E, (1990). An isobolographic analysis of the antinociceptive effect of systemically and intrathecally administered combinations of clonidine and opiates. J Pharmacol Exp Ther 255: 1107-1116.
72. Ossipov MH, Lopez Y, Nichols ML, Bian D, Porreca F, (1995). Inhibition by spinal morphine of the tail-flick response is attenuated in rats with nerve ligation injury. Neurosci Lett 199: 83-86.
73. Ossipov MH, Lopez Y, Bian D, Nichols ML, Porreca F, (1997). Synergistic antinociceptive interactions of morphine and clonidine in rats with nerve-ligation injury. Anesthesiology 86: 196-204.
74. Overland AC, Kitto KF, Chabot-Doré A-J, Rothwell PE, Fairbanks CA, Stone LS, 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.
75. Paech MJ, Pavy TJ, Orlikowski CE, Yeo ST, Banks SL, Evans SF, et al. (2004). Postcesarean analgesia with spinal morphine, clonidine, or their combination. Anesth Analg 98: 1460-1466, table of contents.
76. Park J, Forrest J, Kolesar R, Bhola D, Beattie S, Chu C, (1996). Oral clonidine reduces postoperative PCA morphine requirements. Can J Anaesth 43: 900-906.
77. Patwardhan AM, Berg KA, Akopain AN, Jeske NA, Gamper N, Clarke WP, et al. (2005). Bradykinin-induced functional competence and trafficking of the delta-opioid receptor in trigeminal nociceptors. J Neurosci 25: 8825-8832.
78. Philip F, Kadamur G, Silos RG, Woodson J, Ross EM, (2010). Synergistic activation of phospholipase C-beta3 by Galpha(q) and Gbetagamma describes a simple two-state coincidence detector. Curr Biol 20: 1327-1335.
79. Plummer JL, Cmielewski PL, Gourlay GK, Owen H, Cousins MJ, (1992). Antinociceptive and motor effects of intrathecal morphine combined with intrathecal clonidine, noradrenaline, carbachol or midazolam in rats. Pain 49: 145-152.
80. Pradhan AA, Befort K, Nozaki C, Gavériaux-Ruff C, Kieffer BL, (2011). The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci 32: 581-590.
81. Przesmycki K, Dzieciuch JA, Czuczwar SJ, Kleinrok Z, (1997). Isobolographic analysis of interaction between intrathecal morphine and clonidine in the formalin test in rats. Eur J Pharmacol 337: 11-17.
82. Rainov NG, Heidecke V, Burkert W, (2001). Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Symptom Manage 22: 862-871.
83. 2+ responses by G(alpha)i- and G(alpha)q-coupled G-protein-coupled receptors require a single PLC(beta) isoform that is sensitive to both G(beta)(gamma) and G(alpha)q. J Biol Chem 286: 942-951.
84. Riedl MS, Schnell SA, Overland AC, Chabot-Doré A-J, Taylor AM, Ribeiro-da-Silva A, 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.
85. van Rijn RM, Brissett DI, Whistler JL, (2012). Emergence of functional spinal delta opioid receptors after chronic ethanol exposure. BPS 71: 232-238.
86. Rios C, Gomes I, Devi LA, (2004). Interactions between delta opioid receptors and alpha-adrenoceptors. Clin Exp Pharmacol Physiol 31: 833-836.
87. Roerig SC, (1995). Decreased spinal morphine/clonidine antinociceptive synergism in morphine-tolerant mice. Life Sci 56: PL115-PL122.
88. Roerig SC, Howse KM, (1996). Omega-agatoxin IVA blocks spinal morphine/clonidine antinociceptive synergism. Eur J Pharmacol 314: 293-300.
89. Roerig SC, Lei S, Kitto K, Hylden JK, Wilcox GL, (1992). Spinal interactions between opioid and noradrenergic agonists in mice: multiplicativity involves delta and alpha-2 receptors. J Pharmacol Exp Ther 262: 365-374.
90. Rosin DL, Zeng D, Stornetta RL, Norton FR, Riley T, Okusa MD, et al. (1993). Immunohistochemical localization of alpha 2A-adrenergic receptors in catecholaminergic and other brainstem neurons in the rat. NSC 56: 139-155.
91. Rowan MP, Ruparel NB, Patwardhan AM, Berg KA, Clarke WP, Hargreaves KM, (2009). Peripheral delta opioid receptors require priming for functional competence in vivo. Eur J Pharmacol 602: 283-287.
92. Roy S, Liu HC, Loh HH, (1998). Mu-opioid receptor-knockout mice: the role of mu-opioid receptor in gastrointestinal transit. Brain Res Mol Brain Res 56: 281-283.
93. Scherrer G, Befort K, Contet C, Becker J, Matifas A, Kieffer BL, (2004). The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice. Eur J Neurosci 19: 2239-2248.
94. Scherrer G, Imamachi N, Cao Y-Q, Contet C, Mennicken F, O'Donnell D, et al. (2009). Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 137: 1148-1159.
95. Schuster DJ, Kitto KF, Overland AC, Messing RO, Stone LS, Fairbanks CA, et al. (2013). Protein kinase C (epsilon) is required for spinal analgesic synergy between delta opioid and alpha-2A adrenergic receptor agonist Pairs. J Neurosci 33: 13538-13546.
96. Schuster DJ, Metcalf MD, Kitto KF, Messing RO, Fairbanks CA, Wilcox GL, (2015). Ligand requirements for involvement of PKCε in synergistic analgesic interactions between spinal μ and δ opioid receptors. Br J Pharmacol 172: 642-653.
97. Shi TJ, Winzer-Serhan U, Leslie F, Hokfelt T, (1999). Distribution of alpha2-adrenoceptor mRNAs in the rat lumbar spinal cord in normal and axotomized rats. Neuroreport 10: 2835-2839.
98. Siddall PJ, Molloy AR, Walker S, Mather LE, Rutkowski SB, Cousins MJ, (2000). The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury. Anesth Analg 91: 1493-1498.
99. Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM, et al. (1997). Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci U S A 94: 1544-1549.
100. Spaulding TC, Fielding S, Venafro JJ, Lal H, (1979). Antinociceptive activity of clonidine and its potentiation of morphine analgesia. Eur J Pharmacol 58: 19-25.
101. 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.
102. Stone LS, Wilcox GL, (2004). Alpha-2-adrenergic and opioid receptor additivity in rat locus coeruleus neurons. Neurosci Lett 361: 265-268.
103. Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL, (1997). The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy. J Neurosci 17: 7157-7165.
104. Stone LS, Broberger C, Vulchanova L, Wilcox GL, Hökfelt T, Riedl MS, et al. (1998). Differential distribution of alpha2A and alpha2C adrenergic receptor immunoreactivity in the rat spinal cord. J Neurosci 18: 5928-5937.
105. Stone LS, Vulchanova L, Riedl MS, Wang J, Williams FG, Wilcox GL, et al. (1999). Effects of peripheral nerve injury on alpha-2A and alpha-2C adrenergic receptor immunoreactivity in the rat spinal cord. Neuroscience 93: 1399-1407.
106. Stone LS, Kitto KF, Eisenach JC, Fairbanks CA, Wilcox GL, (2007). ST91 [2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride]-mediated spinal antinociception and synergy with opioids persists in the absence of functional alpha-2A- or alpha-2C-adrenergic receptors. J Pharmacol Exp Ther 323: 899-906.
107. Sullivan AF, Dashwood MR, Dickenson AH, (1987). Alpha 2-adrenoceptor modulation of nociception in rat spinal cord: location, effects and interactions with morphine. Eur J Pharmacol 138: 169-177.
108. Tajerian M, Millecamps M, Stone LS, (2012). Morphine and clonidine synergize to ameliorate low back pain in mice. Pain Res Treat 2012: 150842.
109. Tallarida RJ, (1992). Statistical analysis of drug combinations for synergism. Pain 49: 93-97.
110. Tallarida RJ, (2006). An overview of drug combination analysis with isobolograms. J Pharmacol Exp Ther 319: 1-7.
111. Tan M, Walwyn WM, Evans CJ, Xie C-W, (2009). p38 MAPK and beta-arrestin 2 mediate functional interactions between endogenous micro-opioid and alpha2A-adrenergic receptors in neurons. J Biol Chem 284: 6270-6281.
112. Terrillon S, Bouvier M, (2004). Roles of G-protein-coupled receptor dimerization. EMBO Rep 5: 30-34.
113. Tung AS, Yaksh TL, (1982). In vivo evidence for multiple opiate receptors mediating analgesia in the rat spinal cord. Brain Res 247: 75-83.
114. Vilardaga J-P, Nikolaev VO, Lorenz K, Ferrandon S, Zhuang Z, Lohse MJ, (2008). Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling. Nat Chem Biol 4: 126-131.
115. Walker SM, Goudas LC, Cousins MJ, Carr DB, (2002). Combination spinal analgesic chemotherapy: a systematic review. Anesth Analg 95: 674-715.
116. Wang H-B, Zhao B, Zhong Y-Q, Li K-C, Li Z-Y, Wang Q, et al. (2010). Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons. PNAS 107: 13117-13122.
117. Wei ZY, Roerig SC, (1998). Spinal morphine/clonidine antinociceptive synergism is regulated by protein kinase C, but not protein kinase A activity. J Pharmacol Exp Ther 287: 937-943.
118. Wei ZY, Karim F, Roerig SC, (1996). Spinal morphine/clonidine antinociceptive synergism: involvement of G proteins and N-type voltage-dependent calcium channels. J Pharmacol Exp Ther 278: 1392-1407.
119. Wilcox GL, Carlsson KH, Jochim A, Jurna I, (1987). Mutual potentiation of antinociceptive effects of morphine and clonidine on motor and sensory responses in rat spinal cord. Brain Res 405: 84-93.
120. Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, et al. (2013). Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65: 223-254.
121. Yaksh TL, Rudy TA, (1976). Chronic catheterization of the spinal subarachnoid space. Physiol Behav 17: 1031-1036.
122. Yasuoka S, Yaksh TL, (1983). Effects on nociceptive threshold and blood pressure of intrathecally administered morphine and alpha-adrenergic agonists. Neuropharmacology 22: 309-315.
123. Yekkirala AS, Kalyuzhny AE, Portoghese PS, (2010). Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala 2-MePhe 4-Glyol 5] enkephalin as selective μ-δ agonists. ACS Chem Neurosci 1: 146-154.
124. Zhang X, Bao L, Arvidsson U, Elde R, Hökfelt 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.
125. Zhang YQ, Limbird LE, (2004). Hetero-oligomers of alpha2A-adrenergic and mu-opioid receptors do not lead to transactivation of G-proteins or altered endocytosis profiles. Biochem Soc Trans 32 (Pt 5): 856-860.
126. Zhu Y, King MA, Schuller AG, Nitsche JF, Reidl M, Elde RP, et al. (1999). Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24: 243-252.