Moxonidine, a Mixed α2-Adrenergic and Imidazoline Receptor Agonist, Identifies a Novel Adrenergic Target for Spinal Analgesia

Annals of the New York Academy of Sciences

Volumn 1009, Issue , 2003, Pages 378-385

  Stone, Laura S ^a   Fairbanks, Carolyn A ^a   Wilcox, George L ^a  

^a UNIVERSITY OF MINNESOTA   (United States)

Author keywords

Intrathecal; Pain; Synergy; 2C adrenergic receptor

Indexed keywords

ALPHA 2 ADRENERGIC RECEPTOR; ANALGESIC AGENT; CLONIDINE; IMIDAZOLINE RECEPTOR AGONIST; MOXONIDINE; OPIATE AGONIST; RECEPTOR SUBTYPE; UNCLASSIFIED DRUG;

CLINICAL TRIAL; CONFERENCE PAPER; DRUG INDICATION; DRUG MECHANISM; DRUG POTENTIATION; DRUG TARGETING; HUMAN; NEUROPATHIC PAIN; NONHUMAN; SEDATION; SIDE EFFECT; SPINAL ANESTHESIA; XEROSTOMIA;

EID: 1342305375     PISSN: 00778923     EISSN: None     Source Type: Book Series    
DOI: 10.1196/annals.1304.051     Document Type: Conference Paper

References (77)

1. ARMAH, I.B. & W. STENZEL. 1981. BE-5895, a new clonidine-type antihypertensive aminopyrimidine derivative. Naunyn Schmiedebergs Arch. Pharmacol. 316(Suppl): R-42.
2. PLÄNITZ, V. 1984. Crossover comparison of moxonidine and clonidine in mild to moderate hypertension. Eur. J. Clin. Pharmacol. 27: 147-152.
3. OLLIVIER, J.P. & M.O. CHRISTEN. 1994. I1-imidazoline-receptor agonists in the treatment of hypertension: an appraisal of clinical experience. J. Cardiovasc. Pharmacol. 24:S39-48.
4. KRAFT, K. & H. VETTER. 1994. Twenty-four-hour blood pressure profiles in patients with mild-to-moderate hypertension: moxonidine versus captopril. J. Cardiovasc. Pharmacol. 24: S29-33.
5. KÜPPERS, H.E., B.A. JAGER, J.H. LUSZICK, et al. 1997. Placebo-controlled comparison of the efficacy and tolerability of once-daily moxonidine and enalapril in mild-to-moderate essential hypertension. J. Hypertension 15: 93-97.
6. PILETZ, J.E., H. ZHU & D.N. CHIKKALA. 1996. Comparison of ligand binding affinities at human I-1-Imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. J. Pharmacol. Exp. Ther. 279: 694-702.
7. PAALZOW, L. 1974. Analgesia produced by clonidine in mice and rats. J. Pharm. Pharmacol. 26: 361-363.
8. REDDY, S.V.R., J.L. MADERDRUT & T.L. YAKSH. 1980. Spinal cord pharmacology of adrenergic agonist-mediated antinociception. J. Pharmacol. Exp. Ther. 213: 525-533.
9. REDDY, S.V. & T.L. YAKSH. 1980. Spinal noradrenergic terminal system mediates antinociception. Brain Res. 189: 391-401.
10. YAKSH, T.L. & S.V. REDDY. 1981. Studies in the primate on the analgesic effects associated with intrathecal actions of opiates, alpha-adrenergic agonists and baclofen. Anesthesiology 54: 451-454.
11. EISENACH, J.C., S.Z. LYSAK & C.M. VISCOMI. 1989. Epidural clonidine analgesia following surgery: phase I. Anesthesiology 71: 640-646.
12. EISENACH, J.C., R.L. RAUCK, C. BUZZANELL, et al. 1989. Epidural clonidine analgesia for intractable cancer pain: phase I. Anesthesiology 71: 647-652.
13. MENDEZ, R., J.C. EISENACH & K. KASHTAN. 1990. Epidural clonidine analgesia after cesarean section. Anesthesiology 73: 848-852.
14. RAUCK, R.L., J.C. EISENACH, K. JACKSON, et al. 1993. Epidural clonidine treatment for refractory reflex sympathetic dystrophy. Anesthesiology 79: 1163-1169.
15. EISENACH, J.C., R. D'ANGELO, C. TAYLOR, et al. 1994. An isobolographic study of epidural clonidine and fentanyl after cesarean section. Anesth. Analg. 79: 285-290.
16. EISENACH, J.C., S. DUPEN, M. DUBIOS, et al. 1995. Epidural clonidine analgesia for intractable cancer pain. Pain 61: 391-399.
17. SIDDALL, P.J., M. GRAY, S. RUTKOWSKI, et al. 1994. Intrathecal morphine and clonidine in the management of spinal cord injury pain: a case report. Pain 59: 147-148.
18. COOMBS, D.W., R.L. SAUNDERS, J.D. FRATKIN, et al. 1986. Continuous intrathecal hydromorphone and clonidine for intractable cancer pain. J. Neurosurg. 64: 890-894.
19. PLUMMER, J.L., P.L. CMIELEWSKI, G.K. GOURLAY, et al. 1992. Antinociceptive and motor effects of intrathecal morphine combined with intrathecal clonidine, noradrenaline, carbachol or midazolam. Pain 49: 145-152.
20. WILCOX, G.L., K.H. CARLSSON, A. JOCHIM, et al. 1987. Mutual potentiation of antinociceptive effects of morphine and clonidine on motor and sensory responses in rat spinal cord. Brain Res. 405: 84-93.
21. OSSIPOV, M., S. HARRIS, P. LLOYD, et al. 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.
22. OSSIPOV, M., R. LOZITO, E. MESSINEO, et al. 1990. Spinal antinociceptive synergy between clonidine and morphine, U69593, and DPDPE: isobolographic analysis. Life Sci. 47: PL71-PL76.
23. OSSIPOV, M., S. HARRIS, P. LLOYD, et al. 1990. Antinociceptive interaction between opioids and medetomidine: systemic additivity and spinal synergy. Anesthesiology 73: 1227-1235.
24. SULLIVAN, A.F., M.R. DASHWOOD & A.H. DICKENSON. 1987. α2 adrenoceptor modulation of nociception in rat spinal cord: location, effects and interactions with morphine. Eur. J. Pharmacol. 138: 169-177.
25. DRASNER, K. & H.L. FIELDS. 1988. Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in the rat. Pain 32: 309-312.
26. MONASKY, M.S., A.R. ZINSMEISTER, C.W. STEVENS, et al. 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.
27. YAKSH, T.L. 1985. Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol. Biochem. Behav. 22: 845-858.
28. MONROE, P.J., D.L. SMITH, H.R. KIRK, et al. 1995. Spinal nonadrenergic imidazoline receptors do not mediate the antinociceptive action of intrathecal clonidine in the rat. J. Pharmacol. Exp. Ther. 273: 1057-1062.
29. TAKANO, Y. & T.L. YAKSH. 1992. Characterization of the pharmacology of intrathecally administered alpha-2 agonists and antagonists in rats. J. Pharmacol. Exp. Ther. 261: 764-772.
30. 2C adrenergic receptor immunoreactivity in the rat spinal cord. J. Neurosci. 18: 5928-5937.
31. NICHOLAS, A.P., V. PIERIBONE & T. HOKFELT. 1993. Distributions of mRNAs for alpha-2 adrenergic receptor subtypes in rat brain: an in situ hybridization study. J. Comp. Neurol. 328: 575-594.
32. SHI, T.J.S., U. WINZER-SERHAN, F. LESLIE, et al. 1999. Distribution of alpha(2)-adrenoceptor mRNAs in the rat lumbar spinal cord in normal and axotomized rats. Neuroreport. 10: 2835-2839.
33. SHI, T.J.S., U. WINZER-SERHAN, F. LESLIE, et al. 2000. Distribution and regulation of alpha(2)-adrenoceptors in rat dorsal root ganglia. Pain 84: 319-330.
34. GOLD, M.S., S. DASTMALCHI & J.D. LEVINE. 1997. Alpha 2 adrenergic receptor subtypes in rat dorsal root and superior cervical ganglion neurons. Pain 69: 179-190.
35. ROSIN, D.L., E.M. TALLEY, A. LEE, et al. 1996. Distribution of alpha 2C-adrenergic receptor-like immunoreactivity in the rat central nervous system. J. Comp. Neurol. 372: 135-165.
36. TALLEY, E.M., D.L. ROSIN, A. LEE, et al. 1996. Distribution of alpha 2A-adrenergic receptor-like immunoreactivity in the rat central nervous system. J. Comp. Neurol. 372: 111-134.
37. SCHEININ, M., J.W. LOMASNEY, H.D. HAYDEN, et al. 1994. Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain. Brain Res. Mol. Brain Res. 21: 133-149.
38. ZENG, D.W. & K.R. LYNCH. 1991. Distribution of alpha 2-adrenergic receptor mRNAs in the rat CNS. Brain Res. Mol. Brain Res. 10: 219-225.
39. BLAXALL, H.S., N.A. HASS & D.B. BYLUND. 1994. Expression of alpha 2-adrenergic receptor genes in rat tissues. Receptor 4: 191-199.
40. o neurons by presynaptic alpha-2-adrenergic receptors. J. Neurophysiol. 87: 1938-1947.
41. 2A-adrenoceptor stimulation reduces capsaicin-induced glutamate release from spinal cord synaptosomes. J. Pharmacol. Exp. Ther. 299: 939-944.
42. OLAVE, M.J. & D.J. MAXWELL. 2002. An investigation of neurones that possess the alpha 2C-adrenergic receptor in the rat dorsal horn. Neuroscience 115: 31-40.
43. OLAVE, M.J. & D.J. MAXWELL. 2003. Axon terminals possessing the alpha 2c-adrenergic receptor in the rat dorsal horn are predominantly excitatory. Brain Res. 965: 269-273.
44. 2C-adrenergic receptors. J. Neurosci. 23: 6837-6846.
45. 2A-adrenoceptor subtype mediates antinociception in mice. Eur. J. Pharmacol. 215: 355-356.
46. MILLAN, M.J., K. BERVOETS, J.M. RIVET, et al. 1994. Multiple alpha-2 adrenergic receptor subtypes. II. Evidence for a role of rat R alpha-2A adrenergic receptors in the control of nociception, motor behavior and hippocampal synthesis of noradrenaline. J. Pharmacol. Exp. Ther. 270: 958-972.
47. 2a-adrenergic receptor subtype mediates spinal analgesia evoked by α2 agonists and is necessary for spinal adrenergic/opioid synergy. J. Neurosci. 17: 7157-7165.
48. 2 adrenergic and imidazoline receptor agonist, produces spinal antinociception in mice. J. Pharmacol. Exp. Ther. 290: 403-412.
49. HUNTER, J.C., D.J. FONTANA, L.R. HEDLEY, et al. 1997. Assessment of the role of alpha2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice. Br. J. Pharmacol. 122: 1339-1344.
50. LAKHLANI, P.P., L.B. MACMILLAN, T.Z. GUO, et al. 1997. Substitution of a mutant alpha(2a)-adrenergic receptor via hit and run gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. PNAS 94: 9950-9955.
51. WANG, X.M., Z.J. ZHANG, R. BAINS, et al. 2002. Effect of antisense knock-down of alpha(2a)- and alpha(2c)-adrenoceptors on the antinociceptive action of clonidine on trigeminal nociception in the rat. Pain 98: 27-35.
52. MIZOBE, T., K. MAGHSOUDI, K. SITWALA, et al. 1996. Antisense technology reveals the alpha2A adrenoceptor to be the subtype mediating the hypnotic response to the highly selective agonist, dexmedetomidine, in the locus coeruleus of the rat. J. Clin. Invest. 98: 1076-1080.
53. JANUMPALLI, S., L.S. BUTLER, L.B. MACMILLAN, et al. 1998. A point mutation (D79N) of the α2A adrenergic receptor abolishes the antiepileptogenic action of endogenous norepinephrine. J. Neurosci. 18: 2004-2008.
54. 2a-adrenergic receptor subtype. Science 273: 801-803.
55. TAKANO, Y., M. TAKANO & T.L. YAKSH. 1992. The effect of intrathecally administered imiloxan and WB4101: possible role of α2-adrenoceptor subtypes in the spinal cord. Eur. J. Pharmacol. 219: 465-468.
56. TAKANO, Y. & T.L. YAKSH. 1993. Chronic spinal infusion of dexmedetomidine, ST-91 and clonidine: spinal alpha2 adrenoceptor subtypes and intrinsic activity. J. Pharmacol. Exp. Ther. 264: 327-335.
57. GRAHAM, B.A., D.L. HAMMOND & H.K. PROUDFIT. 2000. Synergistic interactions between two alpha(2)-adrenoceptor agonists, dexmedetomidine and ST-91, in two substrains of Sprague-Dawley rats. Pain 85: 135-143.
58. GUO, T.Z., M.F. DAVIES, W.S. KINGERY, et al. 1999. Nitrous oxide produces antinociceptive response via alpha2B and/or alpha2C adrenoceptor subtypes in mice. Anesthesiology 90: 470-476.
59. SAWAMURA, S., W.S. KINGERY, M.F. DAVIES, et al. 2000. Antinociceptive Action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of α2B adrenoceptors. J. Neurosci. 20: 9242-9251.
60. FAIRBANKS, C.A., I.J. POSTHUMUS, K.F. KITTO, et al. 2000. Moxonidine, a selective imidazoline/a2 adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice. Pain 84: 13-20.
61. FAIRBANKS, C.A., L.S. STONE, K.F. KITTO, et al. 2002. alpha(2C)-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J. Pharmacol. Exp. Ther. 300: 282-290.
62. ARNER, S. & B.A. MEYERSON. 1988. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 33: 11-23.
63. PORTENOY, R.K., K.M. FOLEY & C.E. INTURRISI. 1990. The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain 43: 273-286.
64. DAVIS, K.D., R.D. TREEDE, S.N. RAJA, et al. 1991. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain 47: 309-317.
65. YAKSH, T.L., J.W. POGREL, Y.W. LEE, et al. 1995. Reversal of nerve ligation-induced allodynia by spinal alpha-2 adrenoceptor agonists. J. Pharmacol. Exp. Ther. 272: 207-214.
66. MALMBERG, A.B., L.R. HEDLEY, J.R. JASPER, et al. 2001. Contribution of a2 receptor subtypes to nerve injury-induced pain and its regulation by dexmedetomidine. Br. J. Pharmacol. 132: 1827-1836.
67. HAO, J.X., W. YU, X.J. XU, et al. 1996. Effects of intrathecal vs. systemic clonidine in treating chronic allodynia-like response in spinally injured rats. Brain Res. 736: 28-34.
68. XU, X.J., M.J. PUKE & H.Z. WIESENFELD. 1992. The depressive effect of intrathecal clonidine on the spinal flexor reflex is enhanced after sciatic nerve section in rats. Pain 51: 145-151.
69. POREE, L.R., T.Z. GUO, W.S. KINGERY, et al. 1998. The analgesic potency of dexmedetomidine is enhanced after nerve injury: a possible role for peripheral α2-adrenoceptors. Anesth Analg. 87: 941-948.
70. OSSIPOV, M.H., Y. LOPEZ, D. BIAN, et al. 1997. Synergistic antinociceptive interactions of morphine and clonidine in rats with nerve-ligation injury. Anesthesiology 86: 1-9.
71. FAIRBANKS, C.A., H.O. NGUYEN, B.M. GROCHOLSKI, et al. 2000. Moxonidine, a selective imidazoline-a2-adrenergic receptor agonist, produces spinal synergistic antihyperalgesia with morphine in nerve-injured mice. Anesthesiology 93: 765-773.
72. SHANNON, H.E. & E.A. LUTZ. 2000. Effects of the I-1 imidazoline/alpha(2)-adrenergic receptor agonist moxonidine in comparison with clonidine in the formalin test in rats. Pain 85: 161-167.
73. STONE, L.S., L. VULCHANOVA, M.S. RIEDL, 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.
74. DUFLO, F., X. H. LI, C. BANTEL, et al. 2002. Peripheral nerve injury alters the alpha(2) adrenoceptor subtype activated by clonidine for analgesia. Anesthesiology 97: 636-641.
75. TAN, C.M., M.H. WILSON, L.B. MACMILLAN, et al. 2002. Heterozygous alpha(2A)-adrenergic receptor mice unveil unique therapeutic benefits of partial agonists. Proc. Natl. Acad. Sci. U. S. A. 99: 12471-12476.
76. MICHEL, M.C., L.F. BRASS, A. WILLIAMS, et al. 1989. Alpha 2-adrenergic receptor stimulation mobilizes intracellular Ca2+ in human erythroleukemia cells. J. Biol. Chem. 264: 4986-4891.
77. MOLDERINGS, G.J., H. BONISCH, M. BRUSS, et al. 2000. Species-specific pharmacological properties of human alpha(2A)-adrenoceptors. Hypertension 36: 405-410.