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. 2006 Jun 7;8(2):177–192. doi: 10.1111/j.1527-3458.2002.tb00222.x

RX 821002 as a Tool for Physiological Investigation of α2‐Adrenoceptors

R W Clarke 1,✉, J Harris 1
PMCID: PMC6741674  PMID: 12177687

ABSTRACT

RX 821002 is the 2‐methoxy congener of idazoxan. In binding and tissue studies it behaves as a selective antagonist of α2‐adrenoceptors, with at least 5 times greater affinity for these receptors than any other binding site. It does not select between the different types of α2‐receptor. Although this drug probably has no future as a therapeutic agent, it remains a good probe for physiological activity at α2‐adrenoceptors in animal experiments. A particularly useful feature of this compound is its lack of binding at I1 and I2 imidazoline receptors. However, it has relatively high affinity for 5‐HT1A receptors (at which it acts as an antagonist) and a tendency to behave as an inverse agonist at α2A‐adrenoceptors in some cell culture systems. These potential drawbacks may be overcome by careful design of experiments, and the greater selectivity of RX 821002 renders it much superior to yohimbine or idazoxan as a tool for probing physiological actions at α2‐receptors. It can be compared favorably with other selective antagonists such as atipamezole.

In physiological studies, RX 821002 augments norepinephrine release in the frontal cortex and increases drinking behavior in rat. In rabbit, intrathecal administration of this drug enhances somatic and autonomic motor outflows, showing that tonic adrenergic descending inhibition of withdrawal reflexes and sympathetic pre‐ganglionic neurons is strong in this species. The potentiation of reflexes may be considered a pro‐nociceptive action. In the same model, RX 821002 antagonizes the inhibitory effects of the μ opioid fentanyl, indicating that exogenous opioids synergize with endogenously released norepinephrine in the spinal cord. Thus, the careful use of RX 821002 has revealed several aspects of the physiological activity of α2‐adrenoceptors in rabbit spinal cord and rat brain. We recommend that RX 821002 and/or compounds with similar selectivity for α2‐adrenoceptors (atipamezole, MK‐912, RS‐79948) should be used in preference to yohimbine or idazoxan in all future studies of this type.

Keywords: α2‐Adrenoceptors, Imidazoline receptor, 5‐HT1A receptor, Nociceptive processing, Spinal cord, RX 821002

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References

  • 1. Aantaa R, Marjamaki A, Scheinin M. Molecular pharmacology of α2‐adrenoceptor subtypes. Ann Med 1995;27:439–449. [DOI] [PubMed] [Google Scholar]
  • 2. Berlan M, Montastruc J‐L, Lafontan M. Pharmacological prospects for α2‐ adrenoceptor antagonist therapy. Trends Pharmacol Sci 1992;13:277–282. [DOI] [PubMed] [Google Scholar]
  • 3. Boer GJ, Van der Hee R, Feenstra MGP. α2‐Adrenoceptor assayed in rat brain by the new ligand [3H]RX821002. Biogenic Amines 1993;9:259–269. [Google Scholar]
  • 4. Boronat MA, Olmos G, Garcia Sevilla JA. Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I 2‐imidazoline ligands. Br J Pharmacol 1998;125:175–185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Bousquet P. I 1 receptors, cardiovascular function, and metabolism. Am J Hypertens 2001;14:317S–321S. [DOI] [PubMed] [Google Scholar]
  • 6. Brown CM, MacKinnon AC, Redfern WS, et al. RS‐45041–190: A selective, high‐affinity ligand for I2 imidazoline receptors. Br J Pharmacol 1995;116:1737–1744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Bruban V, Feldman J, Greney H, et al. Respective contributions of alpha‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs. Br J Pharmacol 2001;133:261–266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Callado LF, Gabilondo AM, Meana JJ. [3H]RX821002 (2‐methoxyidazoxan) binds to α2‐adrenoceptor subtypes and a non‐adrenoceptor imidazoline binding site in rat kidney. Eur J Pharmacol 1996;316:359–368. [DOI] [PubMed] [Google Scholar]
  • 9. Calzada BC, De Artinano AA. Alpha‐adrenoceptor subtypes. Pharmacol Res 2001;44:195–208. [DOI] [PubMed] [Google Scholar]
  • 10. Camargo LA, Saad WA. Role of the α1‐ and α2‐adrenoceptors of the paraventricular nucleus on the water and salt intake, renal excretion, and arterial pressure induced by angiotensin II injection into the medial septal area. Brain Res Bull 2001;54:595–602. [DOI] [PubMed] [Google Scholar]
  • 11. Chan SLF, Brown CA, Scarpello KE, Morgan NG. The imidazoline site involved in control of insulin‐secretion: characteristics that distinguish it from I1 and I2 sites. Br J Pharmacol 1994;112:1065–1070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Chan SLF, Scarpello KE, Morgan NG. Identification and characterization of non‐adrenergic binding sites in insulin‐secreting cells with the imidazoline RX821002. Adv Exp Med Biol 1997;426:159–163. [DOI] [PubMed] [Google Scholar]
  • 13. Chapleo CB. The discovery of idazoxan. Chem Brit 1986;22:313–314. [Google Scholar]
  • 14. Clarke RW, Eves S, Harris J, Peachey JE, Stuart E. Interactions between cutaneous afferent inputs to a withdrawal reflex in the decerebrated rabbit and their control by descending and segmental systems. Neurosci. 2002; in press. [DOI] [PubMed] [Google Scholar]
  • 15. Clarke RW, Ford TW, Taylor JS. Adrenergic and opioidergic modulation of a spinal reflex in the rabbit. J Physiol 1988;404:407–417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Clarke RW, Harris J, Houghton AK. Spinal 5‐HT‐receptors and tonic modulation of transmission through a withdrawal reflex pathway in the decerebrated rabbit. Br J Pharmacol 1996;119:1167–1176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Clarke RW, Harris J, Houghton AK. Endogenous adrenergic control of reflexes evoked by mechanical stimulation of the heel in the decerebrated rabbit. Neurosci Lett 2001;308:189–192. [DOI] [PubMed] [Google Scholar]
  • 18. Clarke RW, Harris J, Ogilvie J. Imidazoline I2‐receptors and spinal reflexes in the decerebrated rabbit. Neuropharmacology 2000;39:1904–1912. [DOI] [PubMed] [Google Scholar]
  • 19. Clarke RW, Ogilvie J, Houghton AK. Enhancement and depression of spinal reflexes by 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin in the decerebrated and spinalized rabbit: involvement of 5‐HT1A‐ and non‐5‐HT1A‐receptors. Br J Pharmacol 1997;122:631–638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Clarke RW, Parry‐Baggott C, Houghton AK, Ogilvie J. The involvement of bulbo‐spinal pathways in fentanyl‐induced inhibition of spinal withdrawal reflexes in the decerebrated rabbit. Pain 1998;78:197–207. [DOI] [PubMed] [Google Scholar]
  • 21. Clarke RW, Ward RE. The role of 5‐HT1A‐receptors in fentanyl‐induced bulbospinal inhibition of a spinal withdrawal reflex in the rabbit. Pain 2000;85:239–245. [DOI] [PubMed] [Google Scholar]
  • 22. Clarke RW, Wych BE, Harris J. Adaptive changes in withdrawal reflexes after noxious stimulation at the heel and the toes in the decerebrated rabbit. Neurosci Lett 2001;304:120–122. [DOI] [PubMed] [Google Scholar]
  • 23. Convents A, De Keyser J, De Backer J‐P, Vauquelin G. [3H]Rauwolscine labels α2‐adrenoceptors and 5‐HT1A receptors in human cerebral cortex. Eur J Pharmacol 1989;159:307–310. [DOI] [PubMed] [Google Scholar]
  • 24. Coote JH, Lewis DI. Bulbospinal catecholamine neurones and sympathetic pattern generation. J Physiol Pharmacol 1995;46:259–271. [PubMed] [Google Scholar]
  • 25. Coupland NJ, Bailey JE, Wilson SJ, Potter WZ, Nutt DJ. A pharmacodynamic study of the α2‐adrenergic receptor antagonist ethoxyidazoxan in healthy volunteers. Clin Pharmacol Ther 1994;56:420–429. [DOI] [PubMed] [Google Scholar]
  • 26. Craven JA, Conway EL. Effects of α2‐adrenoceptor antagonists and imidazoline2‐receptor ligands on neuronal damage in global ischaemia in the rat. Clin Exp Pharmacol Physiol 1997;24:204–207. [DOI] [PubMed] [Google Scholar]
  • 27. De Vos H, Czerwiec E, De Backer J‐P, De Potter W, Vauquelin G. [3H]Rauwolscine behaves as an agonist for the 5‐HT1A receptors in human frontal cortex membranes. Eur J Pharmacol 1991;207:1–8. [DOI] [PubMed] [Google Scholar]
  • 28. Devedjian JC, Esclapez F, DenisPouxviel C, Paris H. Further characterization of human α2‐adrenoceptor subtypes: [3H]RX821002 binding and definition of additional selective drugs. Eur J Pharmacol 1994;252:43–49. [DOI] [PubMed] [Google Scholar]
  • 29. Diaz A, Mayet S, Dickenson AH. BU‐224 produces spinal antinociception as an agonist at imidazoline I2 receptors. Eur J Pharmacol 1997;333:9–15. [DOI] [PubMed] [Google Scholar]
  • 30. Docherty JR. Subtypes of functional α1‐ and α2‐adrenoceptors. Eur J Pharmacol 1998;361:1–15. [DOI] [PubMed] [Google Scholar]
  • 31. Doxey JC, Lane AC, Roach AG, Verdee NK. Comparison of the α‐adrenoceptor antagonist profile of idazoxan (RX781094), yohimbine, rauwolscine and corynanthine. Naunyn-Schmiedeberg's Arch Pharmacol 1984;325:136–144. [DOI] [PubMed] [Google Scholar]
  • 32. Eglen RM, Hudson AL, Kendall DA, et al. Seeing through a glass darkly”: casting light on imidazoline “I” sites. Trends Pharmacol Sci 1998;19:381–390. [DOI] [PubMed] [Google Scholar]
  • 33. Erdbrugger W, Raulf M, Otto T, Michel MC. Does [3H]2‐methoxy‐idazoxan (RX 821002) detect more α2‐adrenoceptor agonist high‐affinity sites than [3H]rauwolscine? A comparison of nine tissues and cell lines. J Pharmacol Exp Ther 1995;273:1287–1294. [PubMed] [Google Scholar]
  • 34. Ernsberger P, Graves ME, Graff LM, et al. I1‐imidazoline receptors — Definition, characterization, distribution, and transmembrane signalling. Ann N Y Acad Sci 1995;763:22–42. [DOI] [PubMed] [Google Scholar]
  • 35. Ernsberger P, Meeley MP, Mann JJ, Reis DJ. Clonidine binds to imidazole binding sites as well as α2‐adrenoceptors in the ventrolateral medulla. Eur J Pharmacol 1987;134:1–13. [DOI] [PubMed] [Google Scholar]
  • 36. Fairbanks CA, Posthumus IJ, Kitto KF, Stone LS, Wilcox GL. Moxonidine, a selective imidazoline/α2 adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P‐induced behavior in mice. Pain 2000;84:13–20. [DOI] [PubMed] [Google Scholar]
  • 37. Fairbanks CA, Wilcox GL. Moxonidine, a selective α2‐adrenergic and imidazoline receptor agonist, produces spinal antinociception in mice. J Pharmacol Exp Ther 1999;290:403–412. [PubMed] [Google Scholar]
  • 38. Flamez A, De Backer JP, Czerwiec E, Ladure P, Vauquelin G. Pharmacological characterization of I1 and I2 imidazoline receptors in human striatum. Neurochem Int 1997;30:25–29. [DOI] [PubMed] [Google Scholar]
  • 39. Gobert A, Rivet JM, Audinot V, Newman‐Tancredi A, Cistarelli L, Millan MJ. Simultaneous quantification of serotonin, dopamine and norepinephrine levels in single frontal cortex dialysates of freely‐moving rats reveals a complex pattern of reciprocal auto‐ and heteroreceptor‐mediated control of release. Neurosci 1998;84:413–429. [DOI] [PubMed] [Google Scholar]
  • 40. Goodchild CS, Guo Z, Davies A, Gent JP. Antinociceptive actions of intrathecal xylazine: Interactions with spinal cord opioid pathways. Br J Anaesth 1996;76:544–551. [DOI] [PubMed] [Google Scholar]
  • 41. Gray AM, Pache DM, Sewell RDE. Do α2‐adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds Eur J Pharmacol 1999;378:161–168. [DOI] [PubMed] [Google Scholar]
  • 42. Grijalba B, Callado LF, Meana JJ, Garcia‐Sevilla JA, Pazos A. α2‐Adrenoceptor subtypes in the human brain: A pharmacological delineation of [3H]RX‐821002 binding to membranes and tissue sections. Eur J Pharmacol 1996;310:83–93. [DOI] [PubMed] [Google Scholar]
  • 43. Guyenet PG. Is the hypotensive effect of clonidine and related drugs due to imidazoline binding sites Am J Physiol 1997;42:R1580–R1584. [DOI] [PubMed] [Google Scholar]
  • 44. Haapalinna A, MacDonald E, Viitamaa T, Salonen JS, Sirvio J, Virtanen R. Comparison of the effects of acute and subchronic administration of atipamezole on reaction to novelty and active avoidance learning in rats. Naunyn-Schmiedeberg's Arch Pharmacol 1999;359:194–203. [DOI] [PubMed] [Google Scholar]
  • 45. Haapalinna A, Viitamaa T, MacDonald E, et al. Evaluation of the effects of a specific α2‐adrenoceptor antagonist, atipamezole, on α1 and α2‐adrenoceptor subtype binding, brain neurochemistry and behavior in comparison with yohimbine. Naunyn-Schmiedeberg's Arch Pharmacol 1997;356:570–582. [DOI] [PubMed] [Google Scholar]
  • 46. Hamilton CA, Reid JL, Yakubu MA. [3H]Yohimbine and [3H]Idazoxan bind to different sites on rabbit forebrain and kidney membranes. Eur J Pharmacol 1988;146:345–348. [DOI] [PubMed] [Google Scholar]
  • 47. Harris J, Clarke RW. An analysis of adrenergic influences on the sural gastrocnemius reflex of the decerebrated rabbit. Exp Brain Res 1992;92:310–317. [DOI] [PubMed] [Google Scholar]
  • 48. Harris J, Clarke RW. Motor and cardiovascular effects of selective α2‐adrenoceptor antagonists in the decerebrated rabbit. Eur J Pharmacol 1993;237:323–328. [DOI] [PubMed] [Google Scholar]
  • 49. Herrero JF, Solano RE. The antinociceptive effect of the μ‐opioid fentanyl is reduced in the presence of the α2‐adrenergic antagonist idazoxan in inflammation. Brain Res 1999;840:106–114. [DOI] [PubMed] [Google Scholar]
  • 50. Hieble JP, Bondinell WE, Ruffolo RR. α‐ and β‐Adrenoceptors: From the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification. J Med Chem 1995;38:3415–3444. [DOI] [PubMed] [Google Scholar]
  • 51. Houghton AK, Westlund KN. An I 2 imidazoline ligand, RS 45041, potentiates hyperalgesia in acute arthritis. Neuroreport 1996;7:1497–1501. [DOI] [PubMed] [Google Scholar]
  • 52. Hudson AL, Chapleo CB, Lewis JW, et al. Identification of ligands selective for central I2‐imidazoline binding sites. Neurochem Int 1997;30:47–53. [DOI] [PubMed] [Google Scholar]
  • 53. Hudson AL, Mallard NJ, Tyacke R, Nutt DJ. [3H]‐RX821002: a highly selective ligand for the identification of α2‐adrenoceptors in the rat brain. Molecular Neuropharmacology 1992;1:219–229. [Google Scholar]
  • 54. Hudson AL, Robinson ESJ, Lalies MD, Tyacke RJ, Jackson HC, Nutt DJ. In vitro and in vivo approaches to the characterization of the α2‐adrenoceptor. J Auton Pharmacol 1999;19:311–320. [DOI] [PubMed] [Google Scholar]
  • 55. Hume SP, Ashworth S, Lammertsma AA, et al. Evaluation in rat of RS‐79948–97 as a potential PET ligand for central α2‐adrenoceptors. Eur J Pharmacol 1996;317:67–73. [DOI] [PubMed] [Google Scholar]
  • 56. Hume SP, Lammertsma AA, Opackajuffry J, et al. Quantification of in vivo binding of [3H]RX 821002 in rat brain‐evaluation as a radioligand for central α2‐adrenoceptors. Nucl Med Biol-Int J Rad App B 1992;19:841–849. [DOI] [PubMed] [Google Scholar]
  • 57. Jackson HC, Griffin IJ, Nutt DJ. The effects of idazoxan and other α2‐adrenoceptor antagonists on food and water‐intake in the rat. Br J Pharmacol 1991;104:258–262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Jansson CC, Kukkonen JP, Nasman J, et al. Protean agonism at α2A‐adrenoceptors. Mol Pharmacol 1998;53:963–968. [PubMed] [Google Scholar]
  • 59. Jolkkonen J, Puurunen K, Rantakomi S, Harkonen A, Haapalinna A, Sivenius J. Behavioral effects of the α‐adrenoceptor antagonist, atipamezole, after focal cerebral ischemia in rats. Eur J Pharmacol 2000;400:211–219. [DOI] [PubMed] [Google Scholar]
  • 60. Jones SL. Descending noradrenergic influences on pain. Prog Brain Res 1991;88:381–394. [DOI] [PubMed] [Google Scholar]
  • 61. Kamibayashi T, Maze M. Clinical uses of α2‐adrenergic agonists. Anesthesiol 2000;93:1345–1349. [DOI] [PubMed] [Google Scholar]
  • 62. Karhuvaara S, Kallio A, Scheinin M, Anttila M, Salonen JS, Scheinin H. Pharmacological effects and pharmacokinetics of atipamezole, a novel α2‐adrenoceptor antagonist — A randomized, double‐blind crossover study in healthy male‐volunteers. Br J Clin Pharmacol 1990;30:97–106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Khan ZP, Ferguson CN, Jones RM. α2‐ and imidazoline receptor agonists — Their pharmacology and therapeutic role. Anaesthesia 1999;54:146–165. [DOI] [PubMed] [Google Scholar]
  • 64. Krystal JH, McDougle CJ, Woods SW, Price LH, Heninger GR, Charney DS. Dose‐response relationship for oral idazoxan effects in healthy human subjects — comparison with oral yohimbine. Psychopharmacology (Berl) 1992;108:313–319. [DOI] [PubMed] [Google Scholar]
  • 65. Kukkonen JP, Ge HF, Jansson CC, et al. Different apparent modes of inhibition of α2A‐adrenoceptor by α2‐adrenoceptor antagonists. Eur J Pharmacol 1997;335:99–105. [DOI] [PubMed] [Google Scholar]
  • 66. Lalies MD, Nutt DJ. The effect of a selective I 2‐site ligand, 2‐α2‐benzofuranyl)‐2‐imidazoline, on in vivo noradrenaline release in rat brain. Br J Pharmacol 1995;114:413P. [Google Scholar]
  • 67. Langin D, Lafontan M. [3H]Idazoxan binding at non‐α2‐adrenoceptors in rabbit adipocyte membranes. Eur J Pharmacol 1989;159:199–203. [DOI] [PubMed] [Google Scholar]
  • 68. Langin D, Lafontan M, Stillings MR, Paris H. [3H]RX821002: a new tool for the identification of α2A‐adrenoceptors. Eur J Pharmacol 1989;167:95–104. [DOI] [PubMed] [Google Scholar]
  • 69. Lawhead RG, Blaxall HS, Bylund DB. α2A is the predominant α2 adrenergic receptor subtype in human spinal cord. Anesthesiol 1992;77:983–991. [DOI] [PubMed] [Google Scholar]
  • 70. Lione LA, Nutt DJ, Hudson AL. Characterization and autoradiographical localization of imidazoline2 (I2) sites labelled by [3H]2‐(‐2‐benzofuranyl)‐2‐imidazoline in rat‐brain. Br J Pharmacol 1995;116:P 338. [Google Scholar]
  • 71. Mallard NJ, Hudson AL, Nutt DJ. Characterization and autoradiographical localization of nonadrenoceptor idazoxan binding sites in the rat brain. Br J Pharmacol 1992;106:1019–1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Mateo Y, Meana JJ. Determination of the somatodendritic α2‐adrenoceptor subtype located in rat locus coeruleus that modulates cortical noradrenaline release in vivo. Eur J Pharmacol 1999;379:53–57. [DOI] [PubMed] [Google Scholar]
  • 73. Meana JJ, Callado LF, Pazos A, Grijalba B, Garcia‐Sevilla JA. The subtype‐selective α2‐adrenoceptor antagonists BRL 44408 and ARC 239 also recognize 5‐HT1A receptors in the rat brain. Eur J Pharmacol 1996;312:385–388. [DOI] [PubMed] [Google Scholar]
  • 74. Meana JJ, Mateo Y, Pineda J. Somatodendritic α2A‐adrenoceptors in the locus coeruleus are involved in the modulation of cortical noradrenaline release by the antidepressant desipramine. Naunyn-Schmiedeberg's Arch Pharmacol 1998;358:35–43. [DOI] [PubMed] [Google Scholar]
  • 75. Michel MC, Ernsberger P. Keeping an eye on the I site: imidazoline preferring receptors. Trends Pharmacol Sci 1992;13:369–370. [PubMed] [Google Scholar]
  • 76. Michel MC, Insel PA. Are there multiple imidazoline binding sites Trends Pharmacol Sci 1989;10:342–344. [DOI] [PubMed] [Google Scholar]
  • 77. Miralles A, Olmos G, Sastre M, Barturen F, Martin I, Garcia‐Sevilla JA. Discrimination and pharmacological characterization of I2‐imidazoline sites with [3H]idazoxan and α2 adrenoceptors with [3H]RX821002 α2‐methoxy idazoxan) in the human and rat brains. J Pharmacol Exp Ther 1993;264:1187–1197. [PubMed] [Google Scholar]
  • 78. Murrin LC, Gerety ME, Happe HK, Bylund DB. Inverse agonism at α2‐adrenoceptors in native tissue. Eur J Pharmacol 2000;398:185–191. [DOI] [PubMed] [Google Scholar]
  • 79. Newman‐Tancredi A, Nicolas JP, Audinot V, et al. Actions of α2 adrenoceptor ligands at α2A and 5‐HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for α2A adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 1998;358:197–206. [DOI] [PubMed] [Google Scholar]
  • 80. O'Rourke MF, Blaxall HS, Iversen LJ, Bylund DB. Characterization of [3H]RX821002 binding to α2 adrenergic receptor subtypes. J Pharmacol Exp Ther 1994;268:1362–1367. [PubMed] [Google Scholar]
  • 81. Ogilvie J, Clarke RW. Effect of RX 821002 at 5‐HT1A‐receptors in rabbit spinal cord in vivo. Br J Pharmacol 1998;123:1138–1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82. Ogilvie J, Houghton AK, Bhandari RNB, Clarke RW. Suppression of a withdrawal reflex by chemical stimulation in the periaqueductal gray matter of the decerebrated rabbit: involvement of α2‐adrenoceptors. J Physiol 1996;491:112P. [Google Scholar]
  • 83. Ogilvie J, Simpson DAA, Clarke RW. Tonic adrenergic and serotonergic inhibition of a withdrawal reflex in rabbits subjected to different levels of surgical preparation. Neurosci 1999;89:1247–1258. [DOI] [PubMed] [Google Scholar]
  • 84. Olmos G, Alemany R, Boronat MA, GarciaSevilla JA. Pharmacologic and molecular discrimination of I2‐imidazoline receptor subtypes. Ann NY Acad Sci 1999;881:144–1460. [DOI] [PubMed] [Google Scholar]
  • 85. Olmos G, DeGregorio‐Rocasolano N, Regalado MP, et al. Protection by imidazol(ine) drugs and agmatine of glutamate‐induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor. Br J Pharmacol 1999;127:1317–1326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Parini A, Gargalidis Moudanos C, Pizzinat N, Lanier SM. The elusive family of imidazoline binding sites. Trends Pharmacol Sci 1996;17:13–16. [DOI] [PubMed] [Google Scholar]
  • 87. Pauwels PJ, Tardif S, Wurch T, Colpaert FC. Facilitation of constitutive α2‐adrenoceptor activity by both single amino acid mutation (Thr373Lys) and Gα0 protein coexpression: Evidence for inverse agonism. J Pharmacol Exp Ther 2000;292:654–663. [PubMed] [Google Scholar]
  • 88. Peng YB, Lin Q, Willis WD. Involvement of α2 adrenoceptors in the periaqueductal gray‐induced inhibition of dorsal horn cell activity in rats. J Pharmacol Exp Ther 1996;278:125–135. [PubMed] [Google Scholar]
  • 89. Pettibone DJ, Clineschmidt BV, Lotti VJ, et al. Pharmacological profile of a new potent and specific α2‐adrenoceptor antagonist, L‐657, 743. Naunyn-Schmiedeberg's Arch Pharmacol 1987;336:169–175. [DOI] [PubMed] [Google Scholar]
  • 90. Polidori C, Gentili F, Pigini M, Quaglia W, Panocka I, Massi M. Hyperphagic effect of novel compounds with high affinity for imidazoline I 2 binding sites. Eur J Pharmacol 2000;392:41–49. [DOI] [PubMed] [Google Scholar]
  • 91. Proudfit HK, Clark FM. The projections of locus coeruleus neurons to the spinal cord. Prog Brain Res 1991;88:123–141. [DOI] [PubMed] [Google Scholar]
  • 92. Redfern WS, Williams A. A re‐evaluation of the role of α2‐adrenoceptors in the anxiogenic effects of yohimbine, using the selective antagonist delequamine in the rat. Br J Pharmacol 1995;116:2081–2089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93. Rekling JC, Funk GD, Bayliss DA, Dong XW, Feldman JL. Synaptic control of motoneuronal excitability. Physiol Rev 2000;80:767–852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Rodriguez‐Manzo G. Yohimbine interacts with the dopaminergic system to reverse sexual satiation: further evidence for a role of sexual motivation in sexual exhaustion. Eur J Pharmacol 1999;372:1–8. [DOI] [PubMed] [Google Scholar]
  • 95. Ruffolo RR, Bondinell WE, Hieble JP. α‐Adrenoceptors and β‐adrenoceptors — from the gene to the clinic. 2. Structure‐activity‐relationships and therapeutic applications. J Med Chem 1995;38:3681–3716. [DOI] [PubMed] [Google Scholar]
  • 96. Sagen J, Proudfit HK. Effect of intrathecally‐administered noradrenergic antagonists on nociception in the rat. Brain Res 1984;310:295–301. [DOI] [PubMed] [Google Scholar]
  • 97. Savola MKT, Savola JM. [3H]Dexmedetomidine, an α2‐adrenoceptor agonist, detects a novel imidazole binding site in adult rat spinal cord. Eur J Pharmacol 1996;304:315–323. [DOI] [PubMed] [Google Scholar]
  • 98. Sjoholm B, Lahdesmaki J, Pyykko K, Hillila M, Scheinin M. Non‐adrenergic binding of [3H]atipamezole in rat kidney — regional distribution and comparison to α2‐adrenoceptors. Br J Pharmacol 1999;128:1215–1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99. Sjoholm B, Savola JM, Scheinin M. Nonadrenergic binding of [3H]atipamezole in rat lung. A novel imidazole binding site Ann NY Acad Sci 1995;763:66–77. [DOI] [PubMed] [Google Scholar]
  • 100. Stanfa LC, Dickenson AH. Enhanced α2 adrenergic controls and spinal morphine potency in inflammation. Neuroreport 1994;5:469–472. [DOI] [PubMed] [Google Scholar]
  • 101. Starke K. Presynaptic autoreceptors in the third decade: focus on α2‐adrenoceptors. J Neurochem 2001;78:685–693. [DOI] [PubMed] [Google Scholar]
  • 102. Starke K, Trendelenburg U, Limberger N. Presynaptic α2‐adrenoceptors: Subtype determination. Pharmacol Commun 1995;6:99–108. [Google Scholar]
  • 103. Stillings MR, Chapleo CB, Butler RCM, et al. α‐Adrenoceptor reagents. 3. Synthesis of some 2‐substituted 1,4‐benzodioxans as selective presynaptic α2‐adrenoceptor antagonists. J Med Chem 1985;28:1054–1062. [DOI] [PubMed] [Google Scholar]
  • 104. Stone LS, Broberger C, Vulchanova L, et al. Differential distribution of α2A and α2C adrenergic receptor immunoreactivity in the rat spinal cord. J Neurosci 1998;18:5928–5937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105. Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL. The α2A adrenergic receptor subtype mediates spinal analgesia evoked by α2 agonists and is necessary for spinal adrenergic — opioid synergy. J Neurosci 1997;17:7157–7165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106. Su RB, Li J, Gao K, Pei G, Qin BY. Influence of idazoxan on analgesia, tolerance, and physical dependence of morphine in mice and rats in vivo. Acta Pharmacol Sin 2000;21:1011–1015. [PubMed] [Google Scholar]
  • 107. Trendelenburg AU, Wahl CA, Starke K. Antagonists that differentiate between α2A‐ and α2D‐adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 1996;353:245–249. [DOI] [PubMed] [Google Scholar]
  • 108. Uhlen S, Dambrova M, Nasman J, et al. [3H]RS79948–197 binding to human, rat, guinea pig and pig α2A‐, α2B‐, and α2C‐adrenoceptors. Comparison with MK912, RX821002, rauwolscine and yohimbine. Eur J Pharmacol 1998;343:93–101. [DOI] [PubMed] [Google Scholar]
  • 109. Uhlen S, Lindblom J, Johnson A, Wikberg JES. Autoradiographic studies of central α2A‐ and α2C‐adrenoceptors in the rat using [3H]MK912 and subtype‐selective drugs. Brain Res 1997;770:261–266. [DOI] [PubMed] [Google Scholar]
  • 110. Uhlen S, Lindblom J, Tiger G, Wikberg JES. Quantification of α2A and α2C adrenoceptors in the rat striatum and in different regions of the spinal cord. Acta Physiol Scand 1997;160:407–412. [DOI] [PubMed] [Google Scholar]
  • 111. Uhlen S, Muceniece R, Rangel N, Tiger G, Wikberg JES. Comparison of the binding activities of some drugs on α2A, α2B and α2C‐adrenoceptors and non‐adrenergic imidazoline sites in the guinea pig. Pharmacol Toxicol 1995;76:353–364. [DOI] [PubMed] [Google Scholar]
  • 112. Vauquelin G, De Vos H, De Backer JP, Ebinger G. Identification of α2 adrenergic receptors in human frontal cortex membranes by binding of [3H]RX 821002, the 2‐methoxy analog of [3H]idazoxan. Neurochem Int 1990;17:537–546. [DOI] [PubMed] [Google Scholar]
  • 113. Wade SM, Lan KL, Moore DJ, Neubig RR. Inverse agonist activity at the α2‐adrenergic receptor. Mol Pharmacol 2001;59:532–542. [DOI] [PubMed] [Google Scholar]
  • 114. Welbourn AP, Chapleo CB, Lane AC, et al. α‐Adrenoceptor reagents. 4. Resolution of some potent selective prejunctional α2‐adrenoceptor antagonists. J Med Chem 1986;29:2000–2003. [DOI] [PubMed] [Google Scholar]
  • 115. Wortley KE, Heal DJ, Stanford SC. Modulation of sibutramine‐induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by α2‐adrenoceptors. Br J Pharmacol 1999;128:659–666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116. Wurch T, Colpaert FC, Pauwels PJ. G‐protein activation by putative antagonists at mutant Thr(373)Lys α2A adrenergic receptors. Br J Pharmacol 1999;126:939–948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117. Yaksh TL. Spinal systems and pain processing: development of novel analgesic drugs with mechanistically defined models. Trends Pharmacol Sci 1999;20:329–337. [DOI] [PubMed] [Google Scholar]
  • 118. Yonezawa A, Ando R, Watanabe C, et al. α2A‐Adrenoceptor antagonists. Effects on ejaculation, penile erection and pelvic thrusting behavior in dogs. Pharmacol Biochem Behav 2001;70:141–147. [DOI] [PubMed] [Google Scholar]

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