Cholecystokinin antagonists: Can they augment opioid-derived analgesia?


  • Gary McCleane, MD






Author Biography

Gary McCleane, MD

Rampark Pain Centre, Lurgan, Northern Ireland, United Kingdom.


Boyden EH: Anat Rec. 1926; 33: 162.

Ivy AC, Oldberg E: A hormone mechanism for gall-bladder contraction and evacuation. Am J Physiol. 1928; 86: 599-613.

Rehfeld JF: Immunochemical studies on cholecystokinin. J Biol Chem. 1978; 253: 4022-4030.

Muller JE, Straus E, Yalow RS: Cholecystokinin and its COOH terminal octapeptide in the pig brain. Proc Natl Acad Sci USA. 1977; 74: 3035-3037.

Innis RB, Snyder SH: Distinct cholecystokinin receptors in brain and pancreas. Proc Natl Acad Sci USA. 1980; 77: 6917-6921.

Larsson LI, Rehfeld JF: Localization and molecular heterogeneity of cholecystokinin in the central and peripheral nervous system. Brain Res. 1979; 165: 201-218.

Schiffmann SN, Vanderhaeghen JJ: Distribution of cells containing mRNA encoding cholecystokinin in the rat central nervous system. J Comp Neurol. 1991; 304: 219-233.

Linderfors N, Linden A, Brene S, et al.: CCK peptides and mRNA in the human brain. Prog Neurobiol. 1993; 40: 671-690.

Ossipov MH, Lai J, King T, et al.: Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Bypolimers. 2005; 80: 319-324.

Kuwaara T, Kudoh T, Nakano A, et al.: Species specificity of pharmacological characteristics of CCK B receptors. Neurosci Lett. 1993; 158: 1-4.

Hill DR, Shaw TM, Graham W, et al.: Autoradiographical detection of cholecystokinin A receptors in primate brain using 125I Bolton Hunter CCK 8 and 3H MK329. J Neurosci. 1990; 10: 1070-1081.

Verge VM, Wiesenfeld-Hallin Z, Hokfelt T: Cholecystokinin in mammalian primary sensory neurons and spinal cord: In situ hybridization studies in rat and monkey. Eur J Neurosci. 1993; 5: 240-250.

Zhang X, Dagerlind A, Elde RP, et al.: Marked increase in cholecystokinin B receptor messenger RNA levels in rat dorsal root ganglia after peripheral axotomy. Neuroscience. 1993; 57: 227-233.

Xu X-J, Puke MJ, Verge VM, et al.: Up regulation of cholecystokinin in primary sensory neurons is associated with morphine insensitivity in experimental neuropathic pain in the rat. Neurosci Lett. 1993; 152: 129-132.

Bras JM, Laporte A-M, Benoliel JJ, et al.: Effects of peripheral axotomy on cholecystokinin neurotransmission in the rat spinal cord. J Neurochem. 1999; 72: 858-867.

Gustafsson H, Afrah A, Brodin E, et al.: Pharmacological characterization of morphine induced in vivo release of cholecystokinin in rat dorsal horn: Effects of ion channel blockers. J Neurochem. 1999; 73: 1145-1154.

Zhou Y, Sun Y-H, Zhang Z-W, et al.: Increased release of immunoreactive cholecystokinin octapeptide by morphine and potentiation of mu opioid analgesia by CCK B receptor antagonist L-365,260 in rat spinal cord. Eur J Pharmacol. 1993; 234: 147-154.

Wiesenfeld-Hallin ZA, Lucas G de A, Alster P, et al.: Cholecystokinin/opioid interactions. Brain Res. 1999; 848: 78-89.

Zhou X, Bayer BM: Increases of CCK mRNA and peptide in different brain areas following acute and chronic administration of morphine. Brain Res. 1993; 625: 139-144.

Xu X-J, Alster P, Wu W-P, et al.: Increased level of cholecystokinin in cerebrospinal fluid is associated with chronic painlike behaviour in spinally injured rats. Peptides. 2001; 22: 1305-1308.

Kovelowski CJ, Ossipov MH, Sun H, et al.: Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat. Pain. 2000; 87L: 265-273.

Faris PL, Komisaruk BR, Watkins LR, et al.: Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia. Science. 1983; 219: 310-312.

Schafer M, Zhou L, Stein C: Cholecystokinin inhibits peripheral opioid analgesia in inflamed tissue. Neuroscience. 1998; 82: 603-611.

Watkins LR, Kinscheck LB, Mayer DJ: Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide. Brain Res. 1985; 327: 169-180.

Suh HW, Kim Y-H, Choi YS, et al.: Involvement of different subtypes of cholecystokinin receptors in opioid antinociception in the mouse. Peptides. 1995; 16: 1229-1234.

Lavigne GJ, Millington WR, Mueller GP: The CCK A and CCK B receptor antagonists, Devazepide and L365,260, enhance morphine antinociception only in non-acclimated rats exposed to a novel environment. Neuropeptides. 1992; 21: 119-129.

Nichols ML, Bian D, Ossipov MH, et al.: Regulation of morphine anti allodynic efficacy by cholecystokinin in a rat model of neuropathic pain in rats. J Pharmacol Exp Ther. 1995; 275: 1339-1345.

Coudore-Civiale M-A, Courteix C, Fialip J, et al.: Spinal effect of the cholecystokinin B receptor antagonist CI988 on hyperalgesia, allodynia and morphine induced analgesia in diabetic and mononeuropathic rats. Pain. 2000; 88: 15-22.

Wiesenfeld-Hallin Z, Xu X-J, Hughes J, et al.: PD134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes. Proc Natl Acad Sci USA. 1990; 87: 7105-7109.

Singh L, Oles RJ, Field MJ, et al.: Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine. J Pharmacol. 1996; 118: 1317-1325.

Yamamoto T, Sakashita Y: Differential effects of intrathecally administered morphine and its interaction with cholecystokinin B antagonists on thermal hyperalgesia following two models of experimental mononeuropathy in the rat. Anesthesiology. 1999; 90: 1382-1391.

Zarrindast M-R, Samiee F, Rezayat M: Antinociceptive effect of intracerebroventricular administration of cholecystokinin receptor agonist and antagonist in nerve ligated mice. Pharmacol Ther. 2000; 87: 169-173.

Bodnar RJ, Paul D, Pasternak GW: Proglumide selectively potentiates supraspinal mu opioid analgesia in mice. Neuropharmacology. 1990; 29: 507-510.

Dourish CT, Hawley D, Iversen SD: Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L365,260. Eur J Pharmacol. 1988; 147: 469-472.

Fujimoto JM, Schaus AK, Tseng LF: Spinal dynorphin A: Possible mediator of antianalgesic action in mice. Neuropharmacology. 1990; 29: 609-617.

Wang FS, Rady JJ, Fujimoto JM: Elimination of the antianalgesic action of dynorphin A (1-17) by spinal transection in barbital anesthetized mice. J Pharmacol Exp Ther. 1994; 268: 873-880.

Rady JJ, Holmes BB, Fujimoto JM: Antianalgesic action of dynorphin A mediated by spinal cholecystokinin. Proc Soc Exp Biol Med. 1999; 220: 178-183.

Wang FS, Fujimoto JM: Pentobarbital administered intracerebroventriculary antagonizes morphine induced antinociception in mice. J Pharmacol Exp Ther. 1993; 265: 1361-1368.

Rady JJ, Lin W, Fujimoto JM: Pentobarbital antagonism of morphine analgesia mediated by spinal cholecystokinin. J Pharmacol Exp Ther. 1998; 284: 878-885.

Urban MO, Smith DJ, Gebhart GF: Involvement of spinal cholecystokinin B receptors in mediating neurotensin hyperalgesia from the medullary nucleus raphe magnus in the rat. J Pharmacol Exp Ther. 1996; 278: 90-98.

Urban MO, Smith DJ: Localization of the antinoceptive and antianalgesic effects of neurotensin within the rostral ventromedial medulla. Neurosci Lett. 1994; 174: 21-25.

Urban MO, Smith DJ: Role of neurotensin in the nucleus raphe magnus in opioid-induced antinociception from the periaqueductal gray. J Pharmacol Exp Ther. 1993; 265: 580-586.

Gall C, Lauterborn J, Burks D, et al.: Co-localization of enkephalins and cholecystokinin in discrete areas of rat brain. Brain Res. 1987; 403: 403-408.

Pohl M, Benoliel JJ, Bourgouin S, et al.: Regional distribution of calcitonin gene-related peptide, substance P, cholecystokinin and Met5 enkephalin, and dynorphin A (1-8) like materials in the spinal cord and dorsal root ganglia of adult rats: Effects of dorsal rhizotomy and neonatal capsaicin. J Neurochem. 1990; 55: 1122-1130.

Fournie-Zaluski MC, Coric P, Turcaud S, et al.: Mixed inhibitor prodrug as a new approach towards systemically active inhibitors of enkephalin degrading enzymes. J Med Chem. 1992; 35: 2473-2481.

Valverde O, Maldonado R, Fournie-Zaluski MC, et al.: Cholecystokinin B antagonists strongly potentate antinociception mediated by endogenous enkeophalins. J Pharmacol Exp Ther. 1994; 270: 77-88.

La Guen S, Mas Nieto M, Canestrelli C, et al.: Pain management by a new series of dual enkephalin degrading enzymes: Long lasting antinociceptive properties and potentiation by CCK 2 antagonist or methadone. Pain. 2003; 104(1-2): 139-148.

Vanderah TW, Bernstein RN, Lai JL, et al.: Production of naltindole sensitive antinociception by a cholecystokinin (CCK) antagonist and thiorphan: Evidence for tonic inhibition of enkephalin release by CCK. Analgesia. 1995; 1: 4-6.

Levine JD, Gordon NC, Fields HL: The mechanism of placebo analgesia. Lancet. 1978; 2: 654-657.

Grevert P, Albert LH, Goldstein A: Partial antagonism of placebo analgesia by naloxone. Pain. 1983; 16: 129-143.

Fields HL, Levine JD: Placebo analgesia—A role for endorphins? Trends Neurosci. 1984; 7: 271-273.

Levine JD, Gordon NC: Influence of the method of drug administration on analgesic response. Nature. 1984; 312: 755-756.

Benedetti F: The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain. 1996; 64: 535-543.

Benedetti F, Amanzio M, Maggi G: Potentiation of placebo analgesia by proglumide. Lancet. 1995; 346: 1231.

Hruby VJ, Agnes RS, Davis P, et al.: Design of novel peptide ligands that have opioid agonist activity and CCK antagonist activity for the treatment of pain. Life Sci. 2003; 73: 699-704.

Tang J, Chou J, Iadarola M, et al.: Proglumide prevents and curtails acute tolerance to morphine in rats. Neuro pharmacology. 1984; 23: 715-718.

Panerai AE, Rovati LC, Cocco E, et al.: Dissociation of tolerance and dependence to morphine: A possible role for cholecystokinin. Brain Res. 1987; 410: 52-60.

Tortorici V, Nogueira L, Salas R, et al.: Involvement of local cholecystokinin in the tolerance induced by morphine microinjections into the periaqueductal gray of rats. Pain. 2003; 102: 9-16.

Idanpaan-Heikkila JJ, Guilbaud G, Kayser V: Prevention of tolerance to the antinociceptive effects of systemic morphine by a selective cholecystokinin B receptor antagonist in a rat model of peripheral neuropathy. J Pharmacol Exp Ther. 1997; 282: 1366-1372.

Zarrindast M-R, Nikfar S, Rezayat M: Cholecystokinin receptor mechanism(s) and morphine tolerance in mice. Pharmacol Toxicol. 1999; 84: 46-50.

Zarrindast M-R, Zabihi A, Rezayat M, et al.: Effects of caerulein and CCK antagonists on tolerance induced to morphine antinociception in mice. Pharmacol Biochem Behav. 1997; 58: 173-178.

Dourish CT, O’Neill MF, Coughlan J, et al.: The selective CCK B receptor antagonist L365,260 enhances morphine analgesia and prevents morphine tolerance in the rat. Eur J Pharmacol. 1990; 176: 35-44.

Kissin I, Bright CA, Bradley EL: Acute tolerance to continuously infused alfentanil: The role of cholecystokinin and Nmethyl-D-aspartate nitric oxide systems. Anesth Analg. 2000; 91: 110-116.

Hoffmann O, Wiesenfeld-Hallin Z: The CCK B receptor antagonist CI988 reverses tolerance to morphine in rats. Neuro Report. 1994; 5: 2565-2568.

Watkins LR, Kinscheck IB, Mayer DJ: Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science. 1984; 224: 395-396.

Dourish CT, O’Neill MF, Schafer LW, et al.: The cholecystokinin receptor antagonist Devazepide enhances morphine induced analgesia but not morphine induced respiratory depression in the squirrel monkey. J Phamacol Exp Ther. 1990; 255: 1158-1165.

McCleane GJ: A phase 1 study of the cholecystokinin (CCK) B antagonist L365,260 in human subjects taking morphine for intractable non-cancer pain. Neurosci Lett. 2002; 332: 210-212.

Price DD, von der Gruen A, Miller J, et al.: Potentiation of systemic morphine analgesia in humans by proglumide, a cholecystokinin antagonist. Anesth Analg. 1985; 64: 801-806.

Lavigne GJ, Hargreaves KM, Schmidt EA, et al.: Proglumide potentiates morphine analgesia for acute postsurgical pain. Clin Pharmacol Ther. 1989; 45: 666-673.

Lehmann KA, Schlusener M, Arabatsis P: Failure of proglumide, a cholecystokinin antagonist, to potentiate clinical morphine analgesia. Anesth Analg. 1989; 68: 51-56.

McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain. Anesth Analg. 1998; 87: 1117-1120.

McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine. Clin J Pain. 2003; 19: 200-201.

Bernstein ZP, Yucht S, Battista E, et al.: Proglumide as a morphine adjunct in cancer pain management. J Pain Symptom Manage. 1998; 15: 314-320.

McCleane GJ: A randomised, double blind, placebo controlled crossover study of the cholecystokinin 2 antagonist L365,260 as an adjunct to strong opioids in chronic human neuropathic pain. Neurosci Lett. 2003; 338: 151-154.

McCleane GJ: The cholecystokinin antagonist proglumide reduces analgesic tolerance to morphine in humans with chronic benign pain. Pain Clinic. 1999; 11: 309-312.




How to Cite

McCleane, MD, G. “Cholecystokinin Antagonists: Can They Augment Opioid-Derived Analgesia?”. Journal of Opioid Management, vol. 1, no. 5, Nov. 2005, pp. 273-9, doi:10.5055/jom.2005.0057.



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