CI 988

Spinal effect of the cholecystokinin-B receptor antagonist CI-988 on hyperalgesia, allodynia and morphine-induced analgesia in diabetic and mononeuropathic rats.[Pubmed:11098095]

Pain. 2000 Oct;88(1):15-22.

Since evidence points to the involvement of cholecystokinin (CCK) in nociception, we examined the effect of intrathecal CI-988, an antagonist of the CCK-B receptors, on mechanical hyperalgesia and allodynia in normal, mononeuropathic and diabetic rats,. Owing to the anti-opioid activity of CCK, it has been suggested that hyperactivity in the spinal CCK system is responsible for the low sensitivity of neuropathic pain to opioids. We therefore also evaluated the effect of the combination of i.t. CI-988 + i.v. morphine on mechanical hyperalgesia in diabetic and mononeuropathic rats using isobolographic analysis. Although ineffective in normal rats, CI-988 induced antinociceptive effects in diabetic (290 +/- 20 g with a cut-off of 750 g) and mononeuropathic (117 +/- 16 g; cut-off 750 g) rats, suggesting an involvement of the CCKergic system in neurogenic pain conditions. The combination of CI-988 and morphine showed a superadditive interaction in the diabetic rats only (477 +/- 16 g; cut-off 750 g), in comparison with the antinociceptive effect of each drug. In addition, CI-988 exhibited a weak anti-allodynic effect in mononeuropathic rats, and no anti-allodynic effect in diabetic rats. These results show the CCK-B receptor blockade-mediated antinociceptive effects and reveals the antinociceptive action of morphine in diabetic rats after CCKergic system inhibition.

CI-988 Inhibits EGFR Transactivation and Proliferation Caused by Addition of CCK/Gastrin to Lung Cancer Cells.[Pubmed:25761747]

J Mol Neurosci. 2015 Jul;56(3):663-72.

Cholecystokinin (CCK) receptors are G-protein coupled receptors (GPCR) which are present on lung cancer cells. CCK-8 stimulates the proliferation of lung cancer cells, whereas the CCK2R receptor antagonist CI-988 inhibits proliferation. GPCR for some gastrointestinal hormones/neurotransmitters mediate lung cancer growth by causing epidermal growth factor receptor (EGFR) transactivation. Here, the role of CCK/gastrin and CI-988 on EGFR transactivation and lung cancer proliferation was investigated. Addition of CCK-8 or gastrin-17 (100 nM) to NCI-H727 human lung cancer cells increased EGFR Tyr(1068) phosphorylation after 2 min. The ability of CCK-8 to cause EGFR tyrosine phosphorylation was blocked by CI-988, gefitinib (EGFR tyrosine kinase inhibitor), PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), and tiron (superoxide scavenger). CCK-8 nonsulfated and gastrin-17 caused EGFR transactivation and bound with high affinity to NCI-H727 cells, suggesting that the CCK2R is present. CI-988 inhibited the ability of CCK-8 to cause ERK phosphorylation and elevate cytosolic Ca(2+). CI-988 or gefitinib inhibited the basal growth of NCI-H727 cells or that stimulated by CCK-8. The results indicate that CCK/gastrin may increase lung cancer proliferation in an EGFR-dependent manner.

Effect of the Combination of CI-988 and Morphine on Neuropathic Pain after Spinal Cord Injury in Rats.[Pubmed:25729274]

Korean J Physiol Pharmacol. 2015 Mar;19(2):125-30.

Cholecystokinin is known to be involved in the modulation of nociception and to reduce the efficacy of morphine analgesia. This study investigated the effects of intrathecal administration of morphine and the cholecystokinin type B antagonist CI-988 on below-level neuropathic pain after spinal cord injury in rats. We also examined the interaction of morphine and CI-988 in the antinociceptive effect. Both morphine and CI-988 given individually increased the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner. The combination of ineffective doses of intrathecally administered CI-988 and morphine produced significant analgesic effects and the combination of effective doses resulted in analgesic effects that were greater than the sum of the individual effects of each drug. Thus, morphine showed a synergistic interaction with CI-988 for analgesia of central neuropathic pain.

CI-988 inhibits growth of small cell lung cancer cells.[Pubmed:11714907]

J Pharmacol Exp Ther. 2001 Dec;299(3):1154-60.

The effects of cholecystokinin (CCK) antagonists on small cell lung cancer (SCLC) cells were investigated. CI-988, L-365,260, and L-364,718 inhibited specific (125)I-CCK-8 binding to NCI-H209 cells with IC(50) values of 5, 2, and 200 nM. ([R-(R*,R*)]-4[[2-[[3-(1H-Indole-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1(3,7)]- dec-2-yloxy)carbonyl[amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid) (CI-988; 100 nM) inhibited the ability of 10 nM CCK-8 to elevate cytosolic Ca(2+) in 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'-amino-5'-methylphenoxy )-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester-loaded NCI-H209 cells. By Western blot, CI-988 inhibited tyrosine phosphorylation of focal adhesion kinase and paxillin stimulated by CCK-8. Also, CI-988 inhibited tyrosine phosphorylation of mitogen-activated protein kinase stimulated by CCK-8. By Northern blot, CI-988 antagonized the ability of 10 nM CCK-8 to increase c-fos mRNA in NCI-H209 cells. Also, CI-988 inhibited the ability of CCK-8 to increase vascular endothelial cell growth factor mRNA. Using a [3-(4,5 dimethylthiazol-2-yl)-2.5-diphenyl-2H-tetrazolium bromide] and clonogenic assay, CI-988 inhibited the proliferation of NCI-H209 cells in vitro. Using nude mice, CI-988 inhibited the proliferation of NCI-H209 xenografts. These results suggest that CI-988 is a CCK(2) receptor antagonist that inhibits the proliferation of SCLC cells.

Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: behavioral and biochemical studies.[Pubmed:16135746]

J Neurosci. 2005 Aug 31;25(35):7896-904.

Keeping in mind the increased pain complaints reported in anxious or depressive patients, our goal was to investigate in rats the consequences of an experimentally provoked state of anxiety/depression on pain behavior and on its underlying mechanisms. We therefore used a model of social defeat consisting of a 30 min protected confrontation followed by a 15 min physical confrontation, repeated during 4 d, that elicited symptoms close to those observed in humans with anxiety or depression. Indeed, 5 d later, animals subjected to social-defeat confrontation were characterized by a decrease of sweet-water consumption and of body weight, and a hyperactivity of the hypothalamic-pituitary-adrenal axis, suggesting that the social-defeat procedure induced a prolonged state of anxiety. Rats subjected to the social-defeat procedure showed an enhanced nociceptive behavior to the subcutaneous administration of formalin, 5 d after the last confrontation session. Because chronic treatment with the established anxiolytic chlordiazepoxide (10 mg.kg(-1).d(-1)) prevented hyperalgesia, this strongly suggested that this experimental procedure might be a suitable animal model of "anxiety-induced hyperalgesia." Hyperalgesia associated with anxiety not only was related to a significant increase of CCKLM [cholecystokinin (CCK)-like material] in frontal cortex microdialysates but also was prevented by a CCK-B receptor antagonist [4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[(tricyclo[3.3[12,17]dec-2-yloxy)-car bonyl]amino]-propyl]amino]-1-phenyethyl]amino]-4-oxo-[R-(R*, R*)]-butanoate N-methyl-D-glucamine (CI-988)] (2 mg/kg), strongly supporting the involvement of central CCKergic systems in these phenomena. Finally, combined treatments with CI-988 and morphine completely suppressed pain-related behavior, supporting the idea that the association of both compounds might represent a new therapeutic approach to reduce the increase of pain complaints highly prevalent among anxious or depressive patients.