References

1. Stewart, J. and Badiani, A. (1993) Tolerance and sensitization to the behavioral effects of drugs. Behav. Pharmacol. 4, 289-312.

2. Trujillo, K. A. and Akil, H. (1995) Excitatory amino acids and drugs of abuse: a role for N-methyl-d-aspartate receptors in drug tolerance, sensitization and physical dependence. Drug Alcohol Depend. 38, 139-154.

3. Trujillo, K. A. and Akil, H. (1991) Opiate tolerance and dependence: recent findings and synthesis. New Biol. 3, 915-923.

4. Schulteis, G. and Koob, G. F. (1996) Reinforcement processes in opiate addiction: a homeostatic model. Neurochem. Res. 21,1437-1454.

5. Robinson, T. E. and Berridge, K. C. (1993) The neural basis of drug craving: an incentive-sensitization theory of drug craving. Brain Res. Rev. 18, 247-291.

6. Wolf, M. E. (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog. Neuro-biol. 54, 679-720.

7. Collingridge, G. L. and Watkins, J. C. (1994) The NMDA receptor 2nd ed., Oxford University Press, New York.

8. Meldrum, B. S. (1991) Excitatory amino acid antagonists, in Frontiers in Pharmacology and Therapeutics, Blackwell Scientific, Boston.

9. Seeburg, P. H. (1993) The TINS/TIPS Lecture: the molecular biology of mammalian glutamate receptor channels. Trend Neurosci. 16, 359-365.

10. Collingridge, G. L. and Lester, R. A. J. (1989) Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol. Rev. 41, 143-210.

11. Michaelis, E. K. (1998) Molecular biology of glutamate receptors in the central nervous system and their role in excitotox-icity, oxidative stress and aging. Prog. Neurobiol. 54, 369-415.

12. Yamakura, T. and Shimoji, K. (1999) Subunit- and site-specific pharmacology of the NMDA receptor channel. Prog. Neurobiol. 59, 279-298.

13. Dingledine, R., Borges, K., Bowie, D., and Traynelis, S. F. (1999) The glutamate receptor ion channels. Pharmacol. Rev. 51, 7-61.

14. Artola, A. and Singer, W. (1993) Long-term depression of excitatory synaptic transmission and its relationship to long-term depression. Trends Neurosci. 16, 480-487.

15. McMahon, S. B., Lewin. G. R., and Wall, P. D. (1993) Central hyperexicitability triggered by noxious inputs. Curr. Opin. Neurobiol. 3, 602-610.

16. Malenka, R. C. and Nicoll, R. A. (1993) NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 16, 521-527.

17. Coderre, T. J., Katz, J., Vaccarino, A. L., and Melzack, R. (1993) Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 53, 259-285.

18. McDonald, J. W. and Johnston, M. V. (1990) Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Rev. 15, 41-70.

19. Crepel, V., Congar, P., Aniksztejn, L., et al. (1998) Synaptic plasticity in ischemia: role of NMDA receptors. Prog. Brain Res. 116, 273-285.

20. Abraham, W. C. and Bear, M. F. (1996) Metaplasticity: the plasticity of synaptic plasticity Trends Neurosci. 19, 126-130.

21. Bear, M. F. (1996) NMDA-receptor-dependent synaptic plasticity in the visual cortex. Prog. Brain Res. 108, 205-218.

22. Dickenson, A. H. (1995) Central acute pain mechanisms. Ann. Med. 27, 223-227.

23. Bear, M. F. and Malenka, R. C. (1994) Synaptic plasticity: LTP and LTD. Curr. Opin. Neurobiol. 4, 389-399.

24. Davis, M., Falls, W. A., Campeau, S., and Kim, M. (1993) Fear-potentiated startle: a neural and pharmacological analysis. Behav. Brain Res. 58,175-198.

25. Trujillo, K. A. and Akil, H. (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251, 85-87.

26. Marek, P., Ben-Eliyahu, S., Gold, M., and Liebeskind, J. C. (1991) Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat. Brain Res. 547, 77-81.

27. Marek, P., Ben-Eliyahu, S., Vaccarino, A. L., and Liebeskind, J. C. (1991) Delayed application of MK-801 attenuates development of morphine tolerance in rats. Brain Res. 558,163-165.

28. Trujillo, K. A., Warmoth, K. P., Peterson, D. J., Albertson, D. N., and Swadley-Lewellen, R. M. (2000) NMDA receptor blockade mimics tolerance to the locomotor effects of morphine. International Narcotics Research Conference, Seattle, WA.

29. Bhargava, H. N. and Matwyshyn, G. A. (1993) Dizocilpine (MK-801) blocks tolerance to the analgesic but not to the hyper-thermic effect of morphine in the rat. Pharmacology. 47, 344-350.

30. Gutstein, H. B. and Trujillo, K. A. (1993) MK-801 inhibits the development of morphine tolerance at spinal sites. Brain Res. 626, 332-334.

31. Kest, B., Mogil, J. S., Shamgar, B.-E., et al. (1993) The NMDA receptor antagonist MK-801 protects against the development of morphine tolerance after intrathecal administration. Proc. West. Pharmacol. Soc. 36, 307-310.

32. Lutfy, K., Hurlbut, D. E., and Weber, E. (1993) Blockade of morphine-induced analgesia and tolerance in mice by MK-801. Brain Res. 616, 83-88.

33. Tiseo, P. J. and Inturrisi, C. E. (1993) Attenuation and reversal of morphine tolerance by the competitive N-methyl-d-aspar-tate receptor antagonist LY274614. J. Pharmacol. Exp. Ther. 264,1090-1096.

34. Elliott, K., Minami, N., Kolesnikov, Y. A., Pasternak, G. W., and Inturrisi, C. E. (1994) The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-l-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain 56, 69-75.

35. Mao, J., Price, D. D., and Mayer, D. J. (1994) Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J. Neurosci. 14, 2301-2312.

36. Trujillo, K. A. and Akil, H. (1994) Inhibition of opiate tolerance by non-competitive N-methyl-d-aspartate receptor antagonists. Brain Res. 633,178-188.

37. Mao, J., Price, D. D., Phillips, L. L., Lu, J., and Mayer, D. J. (1995) Increases in protein kinase C immunoreactivity in the spinal cord of rats associated with tolerance to the analgesic effects of morphine. Brain Res. 677, 257-267.

38. Verma, A. and Kulkarni, S. K. (1995) Role of D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptors in morphine tolerance and dependence in mice. Eur. Neuropsychopharmacol 5, 81-87.

39. Bilsky, E. J., Inturrisi, C. E., Sadee, W., Hruby, V. J., and Porreca, F. (1996) Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective | or 8 opioid agonists in mice. Pain 68, 229-237.

40. Dunbar, S. and Yaksh, T. L. (1996) Concurrent spinal infusion of MK801 blocks spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Anesthesiology 84,1177-1188.

41. Lutfy, K., Shen, K. Z., Woodward, R. M., and Weber, E. (1996) Inhibition of morphine tolerance by NMDA receptor antagonists in the formalin test. Brain Res. 731, 171-181.

42. Manning, B. H., Mao, J., Frenk, H., Price, D. D., and Mayer, D. J. (1996) Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance. Pain 67, 79-88.

43. Wong, C.-S., Cherng, C.-H., Luk, H. N., Ho, S.-T., and Tung, C.-S. (1996) Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at |-opioid receptors. Eur. J. Pharmacol. 297, 27-33.

44. Fairbanks, C. A. and Wilcox, G. L. (1997) Acute tolerance to spinally administered morphine compares mechanistically with chronically induced morphine tolerance. J. Pharmacol. Exp. Ther. 282, 1408-1417.

45. Gonzalez, P., Cabello, P., Germany, A., Norris, B., and Contreras, E. (1997) Decrease of tolerance to, and dependence on morphine by, glutamate receptor antagonists. Eur. J. Pharmacol. 332, 257-262.

46. McLemore, G. L., Kest, B., and Inturrisi, C. E. (1997) The effects of LY293558, and AMPA receptor antagonist, on acute and chronic morphine dependence. Brain Res. 778, 120-126.

47. Vaccarino, A. L. and Clavier, M. C. (1997) Blockade of tolerance to stress-induced analgesia by MK-801 in mice. Pharmacol. Biochem. Behav. 56, 435-439.

48. Belozertseva, I. V. and Bespalov, A. (1998) Effects of NMDA receptor channel blockers, dizocilpine and memantine, on the development of opiate analgesic tolerance induced by repeated morphine exposures or social defeats in mice. Naunyn-Schmiedebergs Arch. Pharmacol. 358, 270-274.

49. Larcher, A., Laulin, J. P., Celerier, E., Le Moal, M., and Simonnet, G. (1998) Acute tolerance associated with a single opiate administration: involvement of N-methyl-d-aspartate-dependent pain facilitatory systems. Neuroscience 84, 583-589.

50. McCarthy, R. J., Kroin, J. S., Tuman, K. J., Penn, R. D., and Ivankovich, A. D. (1998) Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats. Anesth. Analg. 86, 830-836.

51. Mao, J., Price, D. D., Lu, J., and Mayer, D. J. (1998) Antinociceptive tolerance to the mu-opioid agonist DAMGO is dose-dependently reduced by MK-801 in rats. Neurosci. Lett. 250, 193-196.

52. Kolesnikov, Y. A. and Pasternak, G. W. (1999) Topical opioids in mice: analgesia and reversal of tolerance by a topical N-methyl-d-aspartate antagonist. J. Pharmacol. Exp. Ther. 290, 247-252.

53. Koyuncuoglu, H., Nurten, A., Yamanturk, P., and Nurten, R. (1999). The importance of the number of NMDA receptors in the develpment of supersensitivity or tolerance to and dependence on morphine. Pharmacol. Res. 39, 311-319.

54. Laulin, J. P., Celerier, E., Larcher, A., Le Moal, M., and Simonnet, G. (1999) Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity. Neuroscience 89, 631-636.

55. Shimoyama, N., Shimoyama, M., Inturrisi, C. E., and Elliott, K. J. (1996) Ketamine attenuates and reverses morphine tolerance in rats. Anesthesiology 85,1357-1366.

56. Kolesnikov, Y. A. and Pasternak, G. W. (1999) Peripheral blockade of topical morphine tolerance by ketamine. Eur. J. Pharmacol. 374, R1-R2.

57. Elliott, K., Hynansky, A., and Inturrisi, C. E. (1994) Dextromethorphan attenuates and reverses analgesic tolerance to morphine. Pain 59, 361-368.

58. Mao, J., Price, D. D., Caruso, F. S., and Mayer, D. J. (1996) Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats. Pain 67, 361-368.

59. Popik, P. and Kozela, E. (1999) Clinically available NMDA antagonist, memantine, attenuates tolerance to analgesic effects of morphine in a mouse tail flick test. Pol. J. Pharmacol. 51, 223-231.

60. Cao, Y. J. and Bhargava, H. N. (1997) Effects of ibogaine on the development of tolerance to antinociceptive action of mu-, delta- and kappa-opioid receptor agonists in mice. Brain Res. 752, 250-254.

61. Davis, A. M. and Inturrisi, C. E. (1999) ¿-Methadone blocks morphine tolerance and N-methyl-d-aspartate-induced hyperalgesia. J. Pharmacol. Exp. Ther. 289,1048-1053.

62. Kolesnikov, Y. A., Ferkany, J., and Pasternak, G. W. (1993) Blockade of mu and kappa opioid analgesic tolerance by NPC17742, a novel NMDA antagonist. Life Sci. 53, 1489-1494.

63. Tiseo, P. J., Cheng, J., Pasternak, G. W., and Inturrisi, C. E. (1994) Modulation of morphine tolerance by the competitive N-methyl-d-aspartate receptor antagonist LY274614: assessment of opioid receptor changes. J. Pharmacol. Exp. Ther. 268, 195-201.

64. Allen, R. M. and Dykstra, L. A. (1999) The competitive NMDA receptor antagonist LY235959 modulates the progression of morphine tolerance in rats. Psychopharmacology 142, 209-214.

65. Allen, R. M., and Dykstra, L. A. (2000) Role of morphine maintenance dose in the development of tolerance and its attenuation by an NMDA receptor antagonist. Psychopharmacology 148, 59-65.

66. Kolesnikov, Y., Maccechini, M. L., and Pasternak, G. W. (1994) 1-Aminocyclopropane carboxylic acid (ACPC) prevents mu and delta opioid tolerance. Life Sci. 55, 1393-1398.

67. Lutfy, K., Shen, K. Z., Kwon, I. S., et al. (1995) Blockade of morphine tolerance by ACEA-1328, a novel NMDA recep-tor/glycine site antagonist. Eur. J. Pharmacol. 273,187-189.

68. Lutfy, K., Doan, P., and Weber, E. (1999) ACEA-1328 a NMDA receptor/glycine site antagonist, acutely potentiates antinociception and chronically attenuates tolerance induced by morphine. Pharmacol. Res. 40, 435-442.

69. Bhargava, H. N. (1994) Diversity of agents that modify opioid tolerance, physical dependence, abstinence syndrome, and self-administrative behavior. Pharmacol. Rev. 46, 293-324.

70. Trujillo, K. A. (2000) Are NMDA receptors involved in opiate-induced neural and behavioral plasticity? A review of preclinical findings. Psychopharmacology 151, 121-141.

71. Herman, B. H., Vocci, F., and Bridge, P. (1995) The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Medication development issues for opiate addiction. Neuropsychopharma-cology 13, 269-293.

72. Inturrisi, C. E. (1997) Preclinical evidence for a role of glutamatergic systems in opioid tolerance and dependence. Semin. Neurosci. 9, 110-119.

73. Pasternak, G. W., Kolesnikov, Y. A., and Babey, A. M. (1995) Perspectives on the N-methyl-d-aspartate/nitric oxide cascade and opioid tolerance. Neuropsychopharmacology 13, 309-313.

74. Jeziorski, M., White, F. J., and Wolf, M. E. (1994) MK-801 prevents the development of behavioral senstization during repeated morphine administration. Synapse 16,137-147.

75. Tzschentke, T. M. and Schmidt, W. J. (1996) Procedural examination of behavioral sensitisation to morphine: lack of blockade by MK-801, occurrence of sensitised sniffing, and evidence for cross-sensitisation between morphine and MK-801. Behav. Pharmacol. 7, 169-184.

76. Swadley-Lewellen, R. M. and Trujillo, K. A. (1998) Are NMDA receptors involved in tolerance and sensitization to the locomotor effects of morphine? Soc. Neurosci. Abstr. 24, 1968.

77. Bespalov, A. Y., Balster, R. L., and Beardsley, P. M. (1999) N-Methyl-d-aspartate receptor antagonists and the development of tolerance to the discriminitive stimulus effects of morphine in rats. J. Pharmacol. Exp. Ther. 290, 20-27.

78. Babbini, M. and Davis, W. M. (1972) Time-dose relationships for locomotor activity effects of morphine after acute or repeated treatment. Br. J. Pharmacol. 46, 213-224.

79. Brady, L. S. and Holtzman, S. G. (1981) Locomotor behavior in morphine-dependent and post-dependent rats. Pharmacol. Biochem. Behav. 14, 361-370.

80. Domino, E. F., Vaski, M. R., and Wilson, A. E. (1976) Mixed depressant and stimulant actions of morphine and their relationship to brain acetylcholine. Life Sci. 18, 361-376.

81. Bartoletti, M., Gairdi, M., Gubellini, C., Bacchi, A., and Babbini, M. (1987) Previous treatment with morphine and sensitization to the excitatory actions of opiates: dose-effect relationship. Neuropharmacology 26, 115-119.

82. Babbini, M., Gaiardi, M., and Bartoletti, M. (1975) Persistence of chronic morphine effects upon activity in rats 8 months after ceasing the treatment. Neuropharmacology. 14, 611-614.

83. Vasko, M. R. and Domino, E. F. (1978) Tolerance development to the biphasic effects of morphine on locomotor activity and brain acetylcholine in the rat. J. Pharmacol. Exp. Ther. 207, 848-858.

84. Swadley-Lewellen, R. M., Watorski, K., Warmoth, K., and Trujillo, K. A. (1998) Acute behavioral interactions between opiates and NMDA receptor antagonists in rats. NIDA Res. Monogr. 179, 95.

85. Trujillo, K. A. and Swadley-Lewellen, R. M. (1997) Tolerance, sensitization and physical dependence to the locomotor effects of morphine in rats. Soc. Neurosci. Abstr. 23, 2413.

86. Trujillo, K. A. and Watorski, K. (1999) Does MK-801 affect the expression of opiate tolerance, sensitization or physical dependence. Soc. Neurosci. Abstr. 25, 2076.

87. Rauhala, P., Idanpaan-Heikkila, J. J., Tuominen, R. K., and Mannisto, P. T. (1994) N-Nitro-l-arginine attenuates development of tolerance to antinociceptive but not to hormonal effects of morphine. Eur. J. Pharmacol. 259, 57-64.

88. Fernandes, M., Kluwe, S., and Coper, H. (1982) Development and loss of tolerance to morphine in the rat. Psychopharma-cology 78, 234-238.

89. Rauhala, P., Idanpaan-Heikkila, J. J., Tuominen, R. K., and Mannisto, P. T. (1995) Differential disappearance of tolerance to thermal, hormonal and locomotor effects of morphine in the male rat. Eur. J. Pharmacol. 285, 69-77.

90. Mannisto, P. T., Borisenko, S. A., Rauhala, P., Tuomainen, P., and Tuominen, R. K. (1994) Variation in tolerance to the antinociceptive, hormonal and thermal effects of morphine after a 5-day pre-treatment of male rats with increasing doses of morphine. Naunyn-Schmiedebergs Arch. Pharmacol. 349, 161-169.

91. Cox, B. M. (1991) Molecular and cellular mechanisms in opioid tolerance, in Towards a New Pharmacotherapy of Pain (Basbaum, A. I. and Besson, J.-M., eds.), Wiley, New York, pp. 137-156.

92. Cox, B. M. and Werling, L. L. (1991) Opioid tolerance and dependence, in The Biological Basis of Drug Tolerance and Dependence, (Pratt, J. A., ed.), Academic, San Diego, CA, pp. 199-229.

93. Trujillo, K. A. (1999) Cellular and molecular and mechanisms of opioid tolerance and dependence: progress and pitfalls. Pain Forum 8, 29-33.

94. Nestler, E. J. and Aghajanian , E. J. (1997) Molecular and cellular basis of addiction. Science 278, 58-63.

95. Wolf, M. E., and Jeziorski, M. (1993) Coadministration of MK-801 with amphetamine, cocaine or morphine prevents rather than transiently masks the development of behavioral sensitization. Brain Res. 613, 291-294.

98. Vanderschuren, L. J., Schoffelmeer, A. N., and De Vries, T. J. (1997) Does dizocilpine (MK-801) inhibit the development of morphine-induced behavioral sensitization in rats? Life Sci. 61, 427-433.

97. Iijima, Y., Asami, T., and Kuribara, H. (1996) Modification by MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, of morphine sensitization: evaluation by ambulation in mice. Jpn. J. Psychopharmacol. 16, 11-18.

96. Livezey, R. T., Pearce, L. B., and Kornetsky, C. (1995) The effect of MK-801 and SCH23390 on the expression and sensiti-zation of morphine-induced oral stereotypy. Brain Res. 692, 93-98.

99. Stephens, D. N. (1995) A glutamatergic hypothesis of drug dependence: extrapolations from benzodiazepine receptor lig-ands. Behav. Pharmacol. 6, 425-446.

100. Kalivas, P. W. (1995) Interactions between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants. Drug Alcohol Depend. 37, 95-100.

101. Ben-Eliyahu, S., Marek, P., Vaccarino, A. L., et al. (1992) The NMDA receptor antagonist MK-801 prevents long-lasting non-associative morphine tolerance in the rat. Brain Res. 575, 304-308.

102. Fundytus, M. E. and Coderre, T. J. (1994) Effects of activity at metabotropic, as well as ionotropic (NMDA), glutamate recepotrs on morphine dependence. Br. J. Pharmacol. 113, 1215-1220.

103. Makimura, M., Sugimoto, H., Shinomiya, K., Kabasawa, Y., and Fukuda, H. (1996) Inhibitory effect of the NMDA receptor antagonist, dizocilpine (MK-801), on the development of morphine dependence. J. Toxicol. Sci. 21, 135-141.

104. Shoemaker, W. J., Kosten, T. A., and Muly, S. M. (1997) Ethanol attenuation of morphine dependence: comparison to dizocilpine. Psychopharmacology 134, 83-87.

105. Laulin, J.-P., Larher, A., Celerier, E., Le Moal, M., and Simonnet, G. (1998) Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time. Eur. J. Neurosci. 10, 782-785.

106. Celerier, E., Laulin, J., Larcher, A., Le Moal, M., and Simonnet, G. (1999) Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Res. 847, 18-25.

107. Celerier, E., Rivat, C., Jun, Y., et al. (2000) Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of keta-mine [see comments]. Anesthesiology 92, 465-472.

108. Zhu, H. and Ho, I. K. (1998) NMDA-R1 antisense oligonucleotide attenuates withdrawal signs from morphine. Eur. J. Pharmacol. 352, 151-156.

109. Koyuncuoglu, H., Gungor, M., Sagduyu, H., and Aricioglu, F. (1990) Suppression by ketamine and dextromethorphan of precipitated abstinence syndrome in rats. Pharmacol. Biochem. Behav. 35, 829-832.

110. Koyuncuoglu, H. and Saydam, B. (1990) The treatment of heroin addicts with dextromethorphan. A double-blind comparison of dextromethorphan with chlorpromazine. Int. J. Clin. Pharmacol. Ther. Toxicol. 28, 147-452.

111. Rasmussen, K., Krystal, J. H., and Aghajanian, G. K. (1991) Excitatory amino acids and morphine withdrawal: differential effects of central and peripheral kynurenic acid administration. Psychopharmacology 105, 508-512.

112. Rasmussen, K., Fuller, R. W., Stockton, M. E., et al. (1991) NMDA receptor antagonists suppress behaviors but not norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal. Eur. J. Pharmacol. 197, 9-16.

113. Tanganelli, S., Antonelli, T., Morari, M., Bianchi, C., and Beani, L. (1991) Glutamate antagonists prevent morphine withdrawal in mice and guinea pigs. Neurosci. Lett. 122, 270-272.

114. Koyuncuoglu, H., Dizdar, Y., Aricioglu, F., and Sayin, U. (1992) Effects of MK-801 on morphine physical dependence: attenuation and intensification. Pharmacol. Biochem. Behav. 43, 487-490.

115. Higgins, G. A., Nguyen, P., and Sellers, E. M. (1992) The NMDA antagonist dizocilpine (MK-801) attenuates motivational as well as somatic aspects of naloxone precipitated opioid withdrawal. Life Sci. 50, PL167-PL172.

116. Brent, P. J., and Chahl, L. A. (1993) Enhancement of the opiate withdrawal response by antipsychotic drugs in guinea pigs is not mediated by sigma binding sites. Eur. Neuropsychopharmacol. 3, 23-32.

117. Cappendijk, S. L. T., de Vries, R., and Dzoljic, M. R. (1993) Excitatory amino acid receptor antagonists and naloxone-pre-cipitated withdrawal syndrome in morphine-dependent mice. Eur. Neuropsychopharmacol. 3, 111-116.

118. Popik, P. and Skolnick, P. (1996) The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence. Pharmacol. Biochem. Behav. 53, 791-797.

119. Popik, P. and Danysz, W. (1997) Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precip-itated opioid withdrawal by N-methyl-d-aspartate receptor antagonist, memantine. J. Pharmacol. Exp. Ther. 280, 854-865.

120. Popik, P., Mamczarz, J., Fraczek, M., et al. (1998) Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists. Neuropharmacology 37, 1033-1042.

121. Bristow, L. J., Hogg, J. E., and Hutson, P. H. (1997) Competitive and glycine/NMDA receptor antagonists attenuate withdrawal-induced behaviors and increased hippocampal acetylcholine efflux in morphine-dependent rats. Neuropharmacology 36, 241-250.

122. Medvedev, I. O., Dravolina, O. A., and Bespalov, A. Y. 1998. Effects of N-methyl-d-aspartate receptor antagonists on discriminative stimulus effects of naloxone in morphine-dependent rats using the Y-maze drug discrimination paradigm. J. Pharmacol. Exp. Ther. 286, 1260-1268.

123. Belozertseva, I. V., Danysz, W., and Bespalov, A. Y. (2000) Short-acting NMDA receptor antagonist MRZ 2/576 produces prolonged suppression of morphine withdrawal in mice. Naunyn-Schmiedebergs Arch. Pharmacol. 361, 279-282.

124. Bläsig, J., Herz, A., Reinhold, K., and Zieglgänsberger, S. (1973) Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacology 33, 19-38.

125. Trujillo, K. A. and Akil, H. (1993) Does MK-801 block naloxone-precipitated opiate withdrawal? Soc. Neurosci. Abstr. 19, 1246.

126. Trujillo, K. A. (1995) Effects of non-competitive N-methyl-d-aspartate receptor antagonists on opiate tolerance and physical dependence. Neuropsychopharmacology 13, 301-307.

127. Popik, P., Kozela, E., and Danysz, W. (2000) Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice. Naunyn-Schmiedebergs Arch. Pharmacol. 361, 425-432.

128. Commons, K. G., van Bockstaele, E. J., and Pfaff, D. W. (1999) Frequent colocalization of mu opioid and NMDA-type glutamate receptors at postsynaptic sites in periaqueductal gray neurons. J. Comp. Neurol. 408, 549-559.

129. Gracy, K. N., Svingos, A. L., and Pickel, V. M. 1997. Dual ultrastructural localization of mu-opioid receptors and NMDA-type glutamate receptors in the shell of the rat nucleus accumbens. J. Neurosci. 17, 4839-4848.

130. Wang, H., Gracy, K. N., and Pickel, V. M. (1999) Mu-opioid and NMDA-type glutamate receptors are often colocalized in spiny neurons within patches of the caudate-putamen nucleus. J. Comp. Neurol. 412, 132-146.

131. Chen, L. and Huang, L. Y. (1991) Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a mu opioid. Neuron 7, 319-326.

132. Chen, L. and Huang, L. Y. (1992) Protein kinase C reduces Mg++ block of NMDA-receptor channels as a mechanism of modulation. Nature 356, 521-523.

133. Fan, G.-H., Zhao, J., Wu, Y. L., et al. (1998) N-Methyl-d-aspartate attenuates opioid receptor-mediated G protein activation and this process involves protein kinase C. Mol. Pharmacol. 53, 684-690.

134. Martin, G., Przewlocki, R., and Siggins, G. R. (1999) Chronic morphine treatment selectively augments metabotropic glutamate receptor-induced inhibition of N-methyl-d-aspartate receptor-mediated neurotransmission in nucleus accumbens. J. Pharmacol. Exp. Ther. 288, 30-35.

135. Martin, G., Nie, Z., and Siggins, G. R. (1997) Mu-Opioid receptors modulate NMDA receptor-mediated responses in nucleus accumbens neurons. J. Neurosci. 17, 11-22.

136. Mao, J., Price, D. D., and Mayer, D. J. (1995) Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 62, 259-274.

137. Mayer, D. J., Mao, J., and Price, D. D. (1995) The association of neuropathic pain, morphine tolerance and dependence, and the translocation of protein kinase C. NIDA Res. Monogr. 147, 269-298.

138. Mayer, D. J. and Mao, J. (1999) Mechanisms of opioid tolerance: a current view of cellular mechanisms. Pain Forum 8, 14-18.

139. Fundytus, M. E. and Coderre, T. J. (1999) Opioid tolerance and dependence: a new model highlighting the role of metabotropic glutamate receptors. Pain Forum 8, 3-13.

140. Mayer, D. J., Mao, J., and Price, D. D. (1995) The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 61, 365-374.

141. Mestek, A., Hurley, J. H., Bye, L. S., et al. (1995) The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C. J. Neurosci. 15, 2396-2406.

142. Narita, M., Makimura, M., Feng, Y., Hoskins, B., and Ho, I. K. (1994) Influence of chronic morphine treatment on protein kinase C activity: comparison with butorphanol and implication for opioid tolerance. Brain Res. 650, 175-179.

143. Makimura, M., Iwai, M., Sugimoto, H., and Fukuda, H. (1997) Effect of NMDA receptor antagonists on protein kinase activated by chronic morphine treatment. J. Toxicol. Sci. 22, 59-66.

144. Ventayol, P., Busquets, X., and Garcia-Sevilla, J. A. (1997) Modulation of immunoreactive protein kinase C-alpha and beta isoforms and G proteins by acute and chronic treatments with morphine and other opiate drugs in rat brain. Naunyn-Schmiedebergs Arch. Pharmacol. 355, 491-500.

145. Li, Y., and Roerig, S. C. (1999) Alteration of spinal protein kinase C expression and kinetics in morphine, but not clonidine, tolerance. Biochem. Pharmacol. 58, 493-501.

146. Smart, D., and Lambert, D. G. (1996) The stimulatory effects of opioids and their possible role in the development of tolerance. Trends Pharmacol. Sci. 17, 264-269.

147. Smith, F. L., Lohmann, A. B., and Dewey, W. L. (1999) Involvement of phospholipid signal transduction in morphine tolerance in mice. Br. J. Pharmacol. 128, 220-226.

148. Smart, D., Hirst, R. A., Hirota, K., Grandy, D. K., and Lambert, D. G. (1997) The effects of recominant rat |-opioid receptor activation in CHO cell on phospholipase C, [Ca2+]i and adenylyl cyclase. Br. J. Pharmacol. 120, 1165-1171.

149. Ueda, H., Miyamae, T., Fukushima, N., et al. (1995) Opioid and K-receptor mediate phospholipase C activation through Gi1 in Xenopus oocytes. Mol. Brain Res. 32, 166-170.

150. Xie, W., Samoriski, G. M., McLaughlin, J. P., et al. (1999) Genetic alterations of phospholipase C ß3 expression modulates behavioral and cellular responses to | opioids. Proc. Natl. Acad. Sci. USA 96,10,385-10,390.

151. Przewlocki, R., Parsons, K. L., Sweeney, D. D., et al. (1999) Opioid enhancement of calcium oscillations and burst events involving NMDA receptors and L-type calcium channels in cultured hippocampal neurons. J. Neurosci. 19, 9705-9715.

152. Narita, M., Narita, M., Mizoguchi, H., and Tseng, L. F. (1995) Inhibition of protein kinase C, but not of protein kinase A, blocks the development of acute antinociceptive tolerance to an intrathecally administered | -opioid receptor agonist in the mouse. Eur. J. Pharmacol. 280, R1-R3.

153. Granados-Soto, V., Kalcheva, I., Hua, X., Newton, A., and Yaksh, T. L. (2000) Spinal PKC activity and expression: role in tolerance produced by continuous spinal morphine infusion. Pain 85, 395-404.

154. Inoue, M., and Ueda, H. (2000) Protein kinase C-mediated acute tolerance to peripheral mu-opioid analgesia in the bradykinin-nociception test in mice. J. Pharmacol. Exp. Ther. 293, 662-669.

155. Fundytus, M. E., and Coderre, T. J. (1996) Chronic inhibition of intracellular Ca2+ release or protein kinase C activation significantly reduces the development of morphine dependence. Eur. J. Pharmacol. 300, 173-181.

156. Xu, J. Y., Hill, K. P., and Bidlack, J. M. (1998) The nitric oxide/cyclic GMP system at the supraspinal site is involved in the development of acute morphine antinociceptive tolerance. J. Pharmacol. Exp. Ther. 284, 196-201.

157. Fan, G.-H., Wang, L.-Z., Qiu, H.-C., Ma, L., and Pei, G. (1999) Inhibition of calcium/calmodulin-dependent protein kinase II in rat hippocampus attenuates morphine tolerance and dependence. Mol. Pharm. 56, 39-45.

158. Cai, Y.-C., Ma, L., Fan, G.-H., et al. (1997) Activation of N-methyl-d-aspartate receptor attenuates acute responsiveness of S-opioid receptors. Mol. Pharm. 51, 583-587.

159. Chen, Y. and Yu, L. (1994) Differential regulation by cAMP-dependent protein kinase and protein kinase C of the | opioid receptor coupling to a G protein-activated K+ channel. J. Biol. Chem. 269, 7839-7842.

160. Zhang, L., Yu, Y., Mackin, S., et al. (1996) Differential | opiate receptor phosphorylation and desensitization induced by agonists and phorbol esters. J. Biol. Chem. 271, 11,449-11,454.

161. Childers, S. (1993) Opioid receptor-coupled second messenger systems, in Opioids I Akil, H. and Simon, E. J., eds.), Springer-Verlag, New York, pp. 189-216.

162. Jordan, B. and Devi, L. A. (1998) Molecular mechanisms of opioid receptor signal transduction. Br. J. Anaesth. 81, 12-19.

163. Law, P.-Y., Wong, Y. H., and Loh, H. H. (2000) Molecular mechanisms and regulation of opioid receptor signalling. Annu. Rev. Pharmacol. Toxicol. 40, 389-430.

164. Wang, L. and Gintzler, A. R. (1995) Morphine tolerance and physical dependence: reversal of opioid inhibition to enhancement of cyclic AMP formation. J. Neurochem. 64,1102-1106.

165. Crain, S. M., and Shen, K.-F. (1990) Opioids can evoke direct receptor-mediated excitatory effects on sensory neurons. Trends Pharmacol. Sci. 11, 77-81.

166. Crain, S. M., and Shen, K.-F. (1998) Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 gan-glioside-regulated opioid receptor functions. Trends Pharmacol. Sci. 19, 358-365.

167. Crain, S. M. and Shen, K.-F. (1996) Modulatory effects of Gs-coupled excitatory opioid receptor functions on opioid analgesia, tolerance and dependence. Neurochem. Res. 21, 1347-1351.

168. Wang, L., Medina, V. M., Rivera, M., and Gintzler, A. R. (1996) Relevance of phosphorylation state to opioid responsiveness in opiate naive and tolerant/dependent tissue. Brain Res. 723, 61-69.

169. Wang, L., and Gintzler, A. R. 1997. Altered mu-opiate receptor-G protein signal transduction following chronic morphine exposure. J. Neurochem. 68, 248-254.

170. Sadee, W. and Wang, Z. (1995) Agonist induced constitutive receptor activation as a novel regulatory mechanism. Mu receptor regulation. Adv. Exp. Med. Biol. 373, 85-90.

171. Wang, Z., Bilsky, E. J., Porreca, F., and Sadee, W. (1994) Constituitive | opioid receptor activation as a regulatory mechanism underlying narcotic tolerance and dependence. Life Sci. 54, PL339-PL350.

172. Martin, G., Ahmed, S. H., Blank, T., et al. (1999) Chronic morphine treatment alters NMDA receptor-mediated synaptic transmission in the nucleus accumbens. J. Neurosci. 19, 9081-9089.

173. Rothman, R. B. (1992) A review of the role of anti-opioid peptides in morphine tolerance and dependence. Synapse 12, 129-138.

174. Trujillo, K. A., Bronstein, D. M., and Akil, H. (1993) Regulation of opioid peptides by self-administered drugs, in The Neurobiology of Opiates (Hammer, R. P., Jr., ed.), CRC, Boca Raton, FL, pp. 223-256.

175. Tiffany, S. T., and Maude-Griffith, P. M. (1988) Tolerance to morphine in the rat: associative and non-associative effects. Behav. Neurosci. 102, 534-543.

176. Dray, A. and Urban, L. (1996) New pharmacological strategies for pain relief. Annu. Rev. Pharmacol. Toxicol. 36, 253-280.

176a. Grass, S., Hoffmann, O., Xu, X. J., and Wiesenfeld, Z. (1996) N-methyl-d-aspartate receptor antagonists potentiate morphine's antinociceptive effect in the rat. Acta Physiol. Scand. 158, 269-273.

177. Hoffmann, O. and Wiesenfeld, Z. (1996) Dextromethorphan potentiates morphine antinociception, but does not reverse tolerance in rats. NeuroReport 7, 838-840.

178. Bespalov, A., Kudryashova, M., and Zvartau, E. (1998) Prolongation of morphine analgesia by competitive NMDA receptor antagonist D-CPPene (SDZ EAA 494) in rats. Eur. J. Pharmacol. 351, 299-305.

179. Advokat, C. and Rhein, F. Q. (1995) Potentiation of morphine-induced antinociception in acute spinal rats by the NMDA antagonist dextrorphan. Brain Res. 699, 157-160.

180. Belozertseva, I. V., Dravolina, O. A., Neznanova, O. N., Danysz, W., and Bespalov, A. Y. 2000. Antinociceptive activity of combination of morphine and NMDA receptor antagonists depends on the inter-injection interval. Eur. J. Pharmacol. 396, 77-83.

181. Goldblum, R. (2000) Long-term safety of MorphiDex. J. Pain Symptom Manage. 19, S50-S56.

182. Chevlen, E. (2000) Morphine with dextromethorphan: conversion from other opioid analgesics. J. Pain Symptom Manage. 19, S42-S49.

183. Katz, N. P. (2000) MorphiDex (MS: DM) double-blind, multiple-dose studies in chronic pain patients. J. Pain Symptom Manage. 19, S37-S41.

184. Caruso, F. S. (2000) MorphiDex pharmacokinetic studies and single-dose analgesic efficacy studies in patients with postoperative pain. J. Pain Symptom Manage. 19, S31-S36.

185. Koyuncuoglu, H. (1995) The combination of tizanidine markedly improves the treatment with dextromethorphan of heroin addicted outpatients. Int. J. Clin. Pharmacol. Ther. 33, 13-19.

186. Rosen, M. I., Pearsall, H. R., and Kosten, T. R. (1998) The effect of lamotrigine on naloxone-precipitated opiate withdrawal. Drug Alcohol Depend. 52, 173-176.

187. Rosen, M. I., McMahon, T. J., Woods, S. W., Pearsall, H. R., and Kosten, T. R. (1996) A pilot study of dextromethorphan in naloxone-precipitated opiate withdrawal. Eur. J. Pharmacol. 307, 251-257.

188. Alper, K. R., Lotsof, H. S., Frenken, G. M., Luciano, D. J., and Bastiaans, J. (1999) Treatment of acute opioid withdrawal with ibogaine. Am. J. Addict. 8, 234-242.

189. Mash, D. C., Kovera, C. A., Buck, B. E., et al. (1998) Medication development of ibogaine as a pharmacotherapy for drug dependence. Ann. N YAcad. Sci. 844, 274-292.

190. Itzhak, Y. and Ali, S. F. (1998) Effect of ibogaine on the various sites of the NMDA receptor complex and sigma binding sites in rat brain. Ann. NY Acad. Sci. 844, 245-251.

191. Layer, R. T., Skolnick, P., Bertha, C. M., et al. (1996) Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors. Eur. J. Pharmacol. 309, 159-165.

192. Popik, P., Layer, R. T., Fossom, L. H., et al. (1995) NMDA antagonist properties of the putative antiaddictive drug, ibogaine. J. Pharmacol. Exp. Ther. 275, 753-760.

193. Popik, P., Layer, R. T., and Skolnick, P. (1995) 100 years of ibogaine: neurochemical and pharmacological actions of a putative anti-addictive drug. Pharmacol. Rev. 47, 235-253.

194. Sheppard, S. G. (1994) A preliminary investigation of ibogaine: case reports and recommendations for further study. J. Subst Abuse Treat. 11, 379-385.

195. Tzschentke, T. M. and Schmidt, W. J. (1995) N-methyl-d-aspartic acid-receptor antagonists block morphine-induced conditioned place preference in rats. Neurosci. Lett. 193, 37-40.

196. Kim, H.-S., Jang, C.-G., and Park, W.-K. (1996) Inhibition by MK-801 of morphine-induced conditioned place preference and postsynaptic dopamine receptor supersensitivity in mice. Pharmacol. Biochem. Behav. 55, 11-17.

197. Del Pozo, E., Barrios, M., and Baeyens, J. M. (1996) The NMDA receptor antagonist dizocilpine (MK-801) stereoselec-tively inhibits morphine-induced place preference conditioning in mice. Psychopharmacology 125, 209-213.

198. Tzschentke, T. M. and Schmidt, W. J. (1997) Interactions of MK-801 and GYKI 52466 with morphine and amphetamine in place preference conditioning and behavioural sensitization. Behav. Brain Res. 84, 99-107.

199. Tzschentke, T. M. and Schmidt, W. J. (1998) Blockade of morphine- and amphetamine-induced conditioned place preference in the rat by riluzole. Neurosci. Lett. 242,114—116.

200. Kotlinska, J. and Biala, G. (1999) Effects of the NMDA/glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced place preference. Pol. J. Pharmacol. 51, 323-330.

201. Suzuki, T., Kato, H., Tsuda, M., Suzuki, H., and Misawa, M. (1999) Effects of the non-competitive NMDA receptor antagonist ifenprodil on the morphine-induced place preference in mice. Life Sci. 64, L151-L156.

202. Semenova, S., Danysz, W., and Bespalov, A. (1999) Low-affinity NMDA receptor channel blockers inhibit acquisition of intravenous morphine self-administration in naive mice. Eur. J. Pharmacol. 378, 1-8.

203. Tzschentke, T. M. and Schmidt, W. J. (2000) Effects of the non-competitive NMDA-receptor antagonist memantine on morphine- and cocaine-induced potentiation of lateral hypothalamic brain stimulation reward. Psychopharmacology 149, 225-234.

204. Carlezon, W. A. and Wise, R. A. (1993) Morphine-induced potentiation of brain stimulation reward is enhanced by MK-801. Brain Res. 620, 339-342.

205. Bubser, M., Keseberg, U., Notz, P. K., and Schmidt, W. J. (1992) Differential behavioral and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur. J. Pharmacol. 229, 75-82.

206. Danysz, W., Essman, U., Bresink, I., and Wilke, R. (1994) Glutamate antagonists have different effects on spontaneous locomotor activity in rats. Pharmacol. Biochem. Behav. 48, 111-118.

207. Hiramatsu, M., Cho, A. K., and Nabeshima, T. (1989) Comparison of the behavioral and biochemical effects of the NMDA receptor antagonists, MK-801 and phencyclidine. Eur. J. Pharmacol. 166, 359-366.

208. Tricklebank, M. D., Singh, L., Oles, R. J., Preston, C., and Iversen, S. D. (1989) The behavioral effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur. J. Pharmacol. 167, 127-135.

209. Newcomer, J. W., Farber, N. B., Jevtovic-Todorovic, V., et al. (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20, 106-118.

210. Jentsch, J. D. and Roth, R. H. (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20, 201-225.

211. Olney, J. W. (1994) Neurotoxicity of NMDA receptor antagonists: an overview. Psychopharmacol. Bull. 30, 533-540.

212. Olney, J. W. and Farber, N. B. (1995) NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. Neuropsychopharmacology 13, 335-345.

213. Domino, E. F. (1990) Status of Ketamine in Anesthesiology, NPP Books, Ann Arbor, MI.

214. Gutstein, H. B., Johnson, K. L., Heard, M. B., and Gregory, G. A. (1992) Oral ketamine preanesthetic medication in children. Anesthesiology 76, 28-33.

215. Krystal, J. H., Karper, L. P., Seibyl, J. P., et al. (1994) Subanesthetic effects of the non-competitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive and neuroendocrine responses. Arch. Gen. Psychiatry 51, 199-214.

216. Marshall, B. E. and Longnecker, D. E. (1996) General anesthetics, in Goodman & Gilman's The Pharmacological Basis of Therapeutics. (Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, K. W., and Gilman, A. G., eds.), McGraw-Hill, New York, pp. 331-348.

217. O'Brien, C. P. (1996) Drug addiction and drug abuse, in Goodman & Gilman's The Pharmacological Basis of Therapeutics (Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W., and Gilman, A. G., eds.), McGraw-Hill, New York, pp. 557-578.

218. Gorelick, D. A. and Balster, R. L. (1995) Phencyclidine (PCP), in Psychopharmacology: The Fourth Generation of Progress (Bloom, F. E. and Kupfer, D. J., eds.), Raven, New York, pp. 1767-1776.

220. Danysz, W. and Parsons, C. G. (1998) Glycine and N-methyl-d-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol. Rev. 50, 597-664.

221. Kemp, J. A. and Leeson, P. D. (1993) The glycine site of the NMDA receptor—five years on. Trends Pharmacol. Sci. 14, 20-25.

222. Lipton, S. A. (1993) Prospects for clinically tolerated NMDA antagonists: open channel blockers and alternative redox states of nitric oxide. Trends Neurosci. 16, 527-532.

223. Rogawski, M. A. and Porter, R. J. (1990) Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol. Rev. 42, 223-286.

224. Rogawski, M. A. (1993) Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodi-azepines. Trends Pharmacol. Sci. 14, 325-331.

225. Parsons, C. G., Danysz, W., and Quack, G. (1999) Memantine is a clinically well-tolerated N-methyl-d-aspartate (NMDA) receptor antagonists—a review of preclinical data. Neuropharmacology 38, 735-767.

226. Willets, J., Balster, R. L., and Leander, J. D. (1990) The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol. Sci. 11, 423-428.

227. Leeson, P. D. and Iversen, L. L. (1994) The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J. Med. Chem. 37, 4053-4065.

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