Pharmacological studies on the central regulation mechanisms for stress response

抄録

Stress-related information is conveyed to the brain, which recruits neuronal and neuroendocrine systems for adaptation to stressful conditions, thereby inducing physical and behavioral responses to stress (stress responses). These responses are both beneficial and deleterious. Transient and proper stress responses are essential for adaptation to stress, while prolonged or excessive activation of the responses could contribute to the development of physical and psychological disorders such as hypertension, peptic ulcer and depression (stress-related disorders). Therefore, it is necessary to clarify the "central" regulation mechanisms for the stress responses in order to prevent stress-mediated exacerbation of these disorders. We have been examining central regulation mechanisms for the sympatho-adrenomedullary system, one of the components of the primary systems for maintaining or reinstating homeostasis during stress exposure. We have found novel roles of brain cannabinoid CB₁ receptors and hemoglobin-derived neuropeptides, hemopressins, in regulation of the sympatho-adrenomedullary outflow, indicating that these molecules may open new avenues of central therapeutic intervention to stress-related disorders by modulating the sympatho-adrenomedullary outflow. In addition, we have been also examining central regulation mechanisms for micturition, because (1) the sympatho-adrenomedullary system can modulate micturition, and (2) stress exacerbates symptoms of bladder dysfunction including overactive bladder and bladder pain syndrome/interstitial cystitis not only in rodent models but also in human patients. By using bombesin, a stress-related neuropeptide, we have found that brain bombesin induces frequent urination through the serotoninergic nervous system, and interestingly, the bombesin-induced response is independent of the sympatho-adrenomedullary outflow activated by bombesin. These findings indicate that brain bombesin and serotonin receptors could be new therapeutic targets for bladder dysfunction exacerbated by stress exposure. There are several concepts regarding bladder function and central control in the normal and pathological condition, however, the exact brain pathophysiological mechanisms underlying stress-induced effects on the bladder are largely unknown. Therefore, our findings could pioneer a novel neuropharmacological field, "Neuro-Uro-Pharmacology".