J Kamei1, M Ohsawa. 1. Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan. kamei@hoshi.ac.jp
Abstract
RATIONALE: Although it is well established that different forms of stress produce a pronounced antinociception, the effect of diabetes on psychological stress-induced antinociception is not yet clear. OBJECTIVES: The effect of diabetes on psychological stress-induced antinociceptive effect was assessed in mice. METHODS: Animals were rendered diabetic by an injection of streptozotocin (200 mg/kg, i.v.). Mice were exposed to psychological stress in the compartment of a communication box. The antinociceptive response was evaluated by the tail-flick test, using radiant heat as a stimulus, which was performed before stress (pre-stress latency) and 0, 30 and 60 min after stress. RESULTS: Exposure to socio-psychological stress for 5, 10 and 15 min produced duration-dependent antinociception in diabetic mice. However, in non-diabetic mice, no appreciable antinociception was found even in the case of socio-psychological stress for 15 min. Pretreatment with diazepam (0.3 mg/kg, i.p.) significantly attenuated socio-psychological stress-induced antinociception in diabetic mice (vehicle: 62.9 +/- 5.5%, n = 10; diazepam: 22 +/- 1%, n = 10). Furthermore, pretreatment with flumazenil (1 mg/kg, i.v.), a benzodiazepine receptor antagonist, also significantly reduced socio-psychological stress-induced antinociception in diabetic mice (vehicle: 77.9 +/- 5.0%, n = 10; flumazenil: 5.8 +/- 1.2%, n = 10). In contrast, pretreatment with methyl beta-carboline-3-carboxylate (beta-CCM, 2 mg/kg, i.v.), a benzodiazepine receptor inverse agonist, significantly enhanced socio-psychological stress-induced antinociception in non-diabetic mice (vehicle: 4.9 +/- 0.6%, n = 10; beta-CCM: 61.5 +/- 5.9%, n = 10), but not in diabetic mice (vehicle: 50.7 +/- 4.5%, n = 10; beta-CCM: 64.4 +/- 7.2%, n = 10). CONCLUSIONS: These results indicate that emotional stress can readily induce antinociception in diabetic mice. Furthermore, this enhanced emotional stress-induced antinociception might be attributable to an increase in the production and/or release of endogenous ligands for benzodiazepine receptors, such as diazepam binding inhibitor, which act as inverse benzodiazepine receptor agonists.
RATIONALE: Although it is well established that different forms of stress produce a pronounced antinociception, the effect of diabetes on psychological stress-induced antinociception is not yet clear. OBJECTIVES: The effect of diabetes on psychological stress-induced antinociceptive effect was assessed in mice. METHODS: Animals were rendered diabetic by an injection of streptozotocin (200 mg/kg, i.v.). Mice were exposed to psychological stress in the compartment of a communication box. The antinociceptive response was evaluated by the tail-flick test, using radiant heat as a stimulus, which was performed before stress (pre-stress latency) and 0, 30 and 60 min after stress. RESULTS: Exposure to socio-psychological stress for 5, 10 and 15 min produced duration-dependent antinociception in diabeticmice. However, in non-diabeticmice, no appreciable antinociception was found even in the case of socio-psychological stress for 15 min. Pretreatment with diazepam (0.3 mg/kg, i.p.) significantly attenuated socio-psychological stress-induced antinociception in diabeticmice (vehicle: 62.9 +/- 5.5%, n = 10; diazepam: 22 +/- 1%, n = 10). Furthermore, pretreatment with flumazenil (1 mg/kg, i.v.), a benzodiazepine receptor antagonist, also significantly reduced socio-psychological stress-induced antinociception in diabeticmice (vehicle: 77.9 +/- 5.0%, n = 10; flumazenil: 5.8 +/- 1.2%, n = 10). In contrast, pretreatment with methyl beta-carboline-3-carboxylate (beta-CCM, 2 mg/kg, i.v.), a benzodiazepine receptor inverse agonist, significantly enhanced socio-psychological stress-induced antinociception in non-diabeticmice (vehicle: 4.9 +/- 0.6%, n = 10; beta-CCM: 61.5 +/- 5.9%, n = 10), but not in diabeticmice (vehicle: 50.7 +/- 4.5%, n = 10; beta-CCM: 64.4 +/- 7.2%, n = 10). CONCLUSIONS: These results indicate that emotional stress can readily induce antinociception in diabeticmice. Furthermore, this enhanced emotional stress-induced antinociception might be attributable to an increase in the production and/or release of endogenous ligands for benzodiazepine receptors, such as diazepam binding inhibitor, which act as inverse benzodiazepine receptor agonists.