devazepide and Pain

Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, N-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1β (IL-1β) production.. In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1β production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1β production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1β in the cancer-inoculated region.. We have identified a novel pain cascade, in which IL-1β production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1β production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival.

Topics: Animals; Benzodiazepinones; Cell Line, Tumor; Devazepide; Disease Models, Animal; Ephrin-B1; Extremities; Ganglia, Spinal; Gene Expression Regulation, Neoplastic; Injections; Interleukin-1beta; Mice; Pain; Pancreatic Neoplasms; Phosphorylation; Receptors, Eph Family; Receptors, N-Methyl-D-Aspartate; Sincalide; Up-Regulation

In this work, the influences of cholecystokinin receptor antagonists L-365,260, MK-329 and proglumide on antinociception induced by baclofen and GABA uptake inhibitor 4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridin-3-ol (THPO) in the tail flick test has been studied. Baclofen and THPO induced antinociception in the tail flick test. Morphine, and the CCK receptor antagonists, MK-329, L-365,260 and proglumide also induced antinociception. The CCK receptor antagonists potentiated antinociceptive response induced by both baclofen and THPO. It may be concluded that cholecystokinin receptor mechanism(s) may interact with antinociception induced by GABA receptor mechanism(s).

Topics: Animals; Baclofen; Benzodiazepinones; Devazepide; Dose-Response Relationship, Drug; Drug Interactions; GABA Agonists; Isoxazoles; Male; Mice; Motor Activity; Pain; Pain Measurement; Phenylurea Compounds; Proglumide; Receptors, Cholecystokinin; Tail

The effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, alone or with a selective cholecystokinin (CCK)B receptor antagonist (CI988) or CCK(A) receptor antagonist (devazepide), on carrageenin-induced spinal c-Fos expression were investigated. Spinal c-Fos expression was observed 90 min after intraplantar carrageenin (6 mg/150 microl saline), with Fos-like-immunoreactive neurons preferentially located in the superficial laminae of the spinal dorsal horn. Intravenous RB101 (10, 20 and 40 mg/kg) dose-dependently reduced the number of superficial Fos-like-immunoreactive neurons (r2 = 0.739, P < .0001), with 63 +/- 2% (P < .0001) reduction for the highest dose. These effects were completely blocked by coadministered naloxone. Coadministration of inactive doses of i.v. RB101 (5 mg/kg) and i.p. CI988 (3 mg/kg) significantly and strongly reduced the number of carrageenin-induced, superficial, Fos-like-immunoreactive neurons (55 +/- 5% reduction of control carrageenin c-Fos expression, P < .0001). This effect was blocked by coadministered naloxone. It is important to note that coadministered RB101 and devazepide did not influence spinal c-Fos expression. None of the various drug combinations influenced the carrageenin-induced peripheral edema. These results show that RB101 dose-dependently decreases carrageenin-evoked spinal c-Fos expression. In addition, the effectiveness of RB101 can be revealed by preadministration of the CCK(B) receptor antagonist CI988. Considering the weak opioid side effects obtained with RB101 treatment and the strong increase of its effects by the CCK(B) receptor antagonist, this type of drug combination could have promising therapeutic application in the management of pain in humans.

Topics: Analgesics; Animals; Benzodiazepinones; Devazepide; Disulfides; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Indoles; Male; Meglumine; Pain; Phenylalanine; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Spinal Cord

The effects of intracerebroventricular administration of the cholecystokinin (CCK) analogue, BDNL, and the selective CCK-B agonist, BC 264, were determined using the hot plate test in mice. BDNL (0.2 nmol and 0.5 nmol) increased the jump and the paw lick latencies. These effects were blocked by the CCK-A antagonist MK-329 (0.02 mg/kg), supporting the involvement of CCK-A receptors in CCK-induced analgesia. In contrast, the selective CCK-B agonist BC 264 produced, at one dose (2.5 nmol), a slight decrease in the lick latency that was only antagonized by the CCK-B antagonist. Naloxone, but not naltrindole, antagonized BDNL-induced analgesia. The results suggest that activation of CCK-A receptors by BDNL leads to antinociceptive responses indirectly mediated by stimulation of mu-opioid receptors by endogenous enkephalins.

Topics: Animals; Benzodiazepinones; Cerebral Ventricles; Cholecystokinin; Devazepide; Hot Temperature; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Naloxone; Pain; Peptide Fragments; Phenylurea Compounds; Receptors, Cholecystokinin; Sincalide

The intracerebroventricular injection of the cholecystokinin-A receptor antagonist L-364,718, at the doses of 0.5, 5, 10 or 20 micrograms/mouse, while having no effect on pain threshold (hot plate, 51 degrees C), antagonized the analgesic activity of morphine (10 mg/kg i.p.). This effect was obtained with a dose of 10 micrograms/mouse and was associated with a reduction of brainstem opiate-binding sites.

Topics: Analgesia; Animals; Benzodiazepinones; Brain Stem; Cholecystokinin; Devazepide; Female; Male; Mice; Morphine; Pain; Receptors, Cholecystokinin; Sensory Thresholds

The effects of the cholecystokinin antagonist devazepide on analgesia and respiratory depression induced by morphine in squirrel monkeys were examined. Pain thresholds were determined using the tail withdrawal procedure, in which monkeys restrained in chairs kept their tails in cool (35 degrees C) water for at least 20 sec, but withdrew them from warm (55 degrees C) water in less than 4 sec. Morphine produced a dose-related increase in tail withdrawal latencies from warm water. Devazepide (injected i.p. or p.o.) had no effect on tail withdrawal latencies when given alone but enhanced the analgesic effects of morphine. The devazepide dose-response curve for morphine enhancement was bell-shaped with doses of 3, 10, 30 and 100 micrograms/kg injected i.p. increasing morphine analgesia whereas higher and lower dose did not. In a separate group of monkeys, morphine produced dose-dependent decreases in respiratory rate and oxygen tension and increases in carbon dioxide tension. In contrast to its effects on morphine analgesia, devazepide had no effect on the various indices of morphine-induced respiratory depression. These data suggest that devazepide may have therapeutic utility as an adjuvant to morphine analgesia allowing lower dose of the opiate to be used to relieve pain and reducing the risk of opiate-induced respiratory depression.

Topics: Administration, Oral; Analgesia; Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Drug Synergism; Injections, Intraperitoneal; Male; Morphine; Naloxone; Pain; Pain Measurement; Receptors, Cholecystokinin; Respiration Disorders; Saimiri

The novel CCK antagonist L364,718 was tested on caerulein- and morphine-induced antinociception in rat using the paw pressure test. Caerulein-induced antinociception (ED50 = 30 micrograms/kg) was significantly inhibited by L354,718 (200 micrograms/kg i.p.) which on its own did not affect paw pressure threshold. In contrast, morphine-induced antinociception was significantly potentiated by L364,718. Since L364,718 is highly selective for 'peripheral' receptors which are found in tissue such as pancreas and gallbladder and a few discrete areas of brain, this receptor is likely to be implicated in the antinociceptive effect of caerulein.

Topics: Analgesics; Animals; Benzodiazepinones; Ceruletide; Cholecystokinin; Devazepide; Drug Interactions; Female; Morphine; Pain; Rats; Rats, Inbred Strains; Reaction Time; Sensory Thresholds