The kappa opioid receptor agonist SA14867 has antinociceptive and weak sedative effects in models of acute and chronic pain.

We examined the analgesic effect of the selective kappa opioid receptor agonist SA14867 and the balance of its antinociceptive and sedative effects. The ED(50) values of SA14867 after oral administration for acetic acid-induced writhing, first and second phases of the formalin test, and rotarod test in mice were 6.1, 9.3, 2.7, and 19.5mg/kg, respectively. These values were smaller than those of the conventional kappa receptor agonists asimadoline and U-50488H. However, the balance of the antinociceptive and sedative effects of SA14867 was better than those of the other two drugs. Orally administered SA14867 (0.1-1mg/kg) significantly improved the decreased pain threshold in a specific alternation of rhythm in an environmental temperature (SART)-stressed model by prophylactic and therapeutic treatment. Improvement in the decreased pain threshold of SA14867-treated animals was attenuated by the opioid receptor antagonist naloxone. Furthermore, orally administered asimadoline (10-100mg/kg) improved the decreased pain threshold in a SART-stressed model, but the doses were close to those known to induce sedative effects. In addition, SA14867 (0.1-1mg/kg) significantly inhibited the arthritis-induced decrease in the pain threshold. Subcutaneously administered morphine (0.1-1mg/kg) improved the decreased pain threshold in a SART-stressed model; on the contrary, morphine did not inhibit the arthritis-induced decrease in the pain threshold. Moreover, orally administered SA14867 (0.1-1mg/kg) strongly attenuated mechanical allodynia and thermal hyperalgesia in a sciatic nerve ligation model. These results suggest that SA14867 has analgesic effects on chronic pain and may serve as a new therapeutic agent for pain treatment.

Effects of the α1-adrenoceptor agonist phenylephrine on SART stress-induced orthostatic hypotension in rats.

BACKGROUND: Specific alternation of rhythm in temperature (SART)-stressed rats, an animal model of autonomic imbalance, exhibit low blood pressure and tachycardia during consciousness and under anesthesia. In addition, these rats easily develop orthostatic hypotension (OH) as a response to postural manipulation. Hence, we studied the influence of the adrenalin α1-receptor agonist phenylephrine on stress-induced OH in SART-stressed rats and unstressed rats. METHODS: Male Wistar rats weighing 250-300 g were used. Rats were fixed in the supine position under urethane anesthesia. Blood pressure was directly measured from the left common carotid artery and ECG was recorded simultaneously. RESULTS: The maximum decrease in blood pressure and the area under the blood pressure-time curve were both large, while the %reflex was small in the SART-stressed rats compared with unstressed rats. In the SART-stressed rats, prolonged intravenous administration of phenylephrine reduced OH at a dose that barely affected unstressed rats. CONCLUSION: The results suggested that sympathetic dysfunction is a factor underlying SART stress-induced OH.

Specific alternation of rhythm in temperature (SART) stress-induced irritable bowel syndrome-like changes in mice and effects of drugs.

Stress is closely associated with the manifestation and progress of irritable bowel syndrome (IBS). For the purpose of establishing experimentally the relationship between IBS and stress, the transportation capacity of the small intestine in specific alternation of rhythm in temperature (SART)-stressed animals was studied using charcoal transportation method. The charcoal suspension was administered orally into the stomach of fasting mice. Mice were sacrificed after a certain time and %charcoal transit (%CT) of the small intestine was measured. The %CTs in SART-stressed mice were greater than those in unstressed or continuously cold-stressed mice. This increase in %CT remained for 1 week after discontinuation of SART stress loading. Cholinergic blockers decreased %CTs in SART-stressed mice. Increases in %CT by a cholinesterase inhibitor were less in SART-stressed mice than in unstressed mice. Increases of %CT in SART-stressed mice were suppressed by Neurotropine. These results suggested that the parasympathetic hypertonicity, not just cold, played a role in the increases in the transportation capacity in SART-stressed mice and that these animals can be a useful tool for elucidation of the mechanism of IBS.

Effects of some beta-adrenoceptor antagonists on orthostatic hypotension in repeatedly cold- (SART-) stressed rats.

Rats stressed by specific alternation of rhythm in temperature (SART) show various symptoms of disautonomia, increased pulse rates, continuous hypotension, and severe orthostatic hypotension (OH) when they are subjected to postural change. The OH symptoms are improved by muscarinic M2-receptor blockers. In the present study, effects of beta-adrenoceptor blocking agents on OH in SART-stressed rats were investigated. Anesthetized rats were restrained on a board in the supine position, and direct blood pressure and ECG were measured automatically using Fluclet Jr.2. Postural change was performed by raising the rat's head up to a 60 degrees angle for 4 min. Unstressed rats treated with hexamethonium showed large decrease in blood pressure, small reflex from the bottom of pressure and decreased tachycardia reflex, whereas isoproterenol showed little changes. In SART-stressed rats, isoproterenol alleviated the decrease in blood pressure in postural change, brought large reflex from the bottom of pressure and increased tachycardia reflex, whereas hexamethonium had little changes. Propranolol and atenolol induced the similar changes as those seen by hexamethonium. ICI-118,551, a selective beta2-adrenoceptor antagonist showed large reflex from the bottom of pressure and increased tachycardia reflex in stressed rats, whereas little changes in unstressed rats. In conclusion, it was suggested that the hypotension in OH manifestation time of rats reflects the state of peripheral blood vessels, and beta1-adrenoceptors played a role in compensatory tachycardia reflex and beta2-adrenoceptors in blood pressure reflex. The circulatory regulation in SART-stressed rats seems to be poorly functioning in nervous reflex in postural changes.

Studies on the variation in clinical laboratory data and safety evaluation of pharmaceuticals.

The safety of pharmaceuticals has become increasingly important not only in daily medical treatment but also in clinical trials. Although clinical laboratory data are more objective than clinical symptoms, the determination as to whether they indicate abnormal variations depends largely upon the clinical judgment of physicians. The process of determination has not been sufficiently objectified. The present study investigated the indices of criteria for variations in clinical laboratory data obtained in clinical trials. Then, detection rates of abnormal variations were compared between our determination method that employs the reference change value (RCV) expressing the width of biological variation for each test component and conventional determination methods. The study also demonstrated that by combining standard values and the RCV for determination, abnormal variations were found at a rate greater than 50%. The method we propose was applied to the safety evaluation of pharmaceuticals. In clinical trials on the antiviral drug ribavirin administered alone, components of laboratory tests were selected that should be noted in studies on its effects. Expect for decreases in red blood cell counts and hemoglobin values, which are closely associated with anemic symptoms and well known to hepatologists, the increasing trend in platelet counts and decreasing trend in albumin were found to be laboratory test components that should be paid attention to, even though they may not be obvious.

Effects of AF-DX116 and other muscarinic receptor antagonists on orthostatic hypotension in autonomic imbalanced (SART-stressed) rats.

SART (specific alternation of rhythm in temperature)-stressed rats are an animal model of autonomic imbalance created by exposing animals to repeated cold stress. The SART-stressed rats have been shown to easily develop orthostatic hypotension (OH). In this study, effects of AF-DX116, a selective M(2) antagonist, and other muscarinic receptor antagonists on OH were investigated in SART-stressed and unstressed rats. Each anesthetized rat was canulated into the left common carotid artery, and blood pressure (BP) and heart rate were measured. Stimulation for postural change was initiated by head-up tilting. As the indices of OH, the maximum fall of BP, % reflex (recovery from maximum fall), and the area enclosed between the baseline and the recovery curve for BP (AUC) were used. Large AUC and small % reflex in SART-stressed rats were changed, becoming similar to those of the unstressed rats by AF-DX116 and methoctoramine. Atropine and methylatropine had similar effects to AF-DX116. However, the effects of methoctoramine, atropine, and methylatropine were less than that of AF-DX116. Pirenzepine was not effective. In conclusion, it was suggested in SART-stressed rats that OH was related to hyperactivity in the parasympathetic nerve and the M(2) receptor played the major role in OH.

A role for corticotropin-releasing factor in repeated cold stress-induced anxiety-like behavior during forced swimming and elevated plus-maze tests in mice.

SART (specific alternation of rhythm in temperature) stress is known to cause anxiety-like behavior in mice/rats in several anxiety-related behavioral tests. In the present study, we investigated possible roles for corticotropin-releasing factor (CRF) and glucocorticoids in SART stress-induced anxiety-like behavior in two different anxiety-related behavioral tests. In the forced swimming test, CRF, administered intracerebroventricular (i.c.v.) at 0.5-2 pmol/mouse, dose-dependently reduced immobility time in unstressed and SART-stressed mice. alpha-Helical CRF, a specific CRF receptor antagonist, administered i.c.v. at 0.1-1 nmol/mouse, dose-dependently increased immobility time in SART-stressed mice, but not in unstressed mice. In the elevated plus-maze test, CRF at 10-20 pmol/mouse significantly decreased the time spent in open arms in unstressed mice. CRF at a high dose tended to decrease this time in SART-stressed mice, but this decrease was not statistically significant. alpha-Helical CRF failed to modify the time in unstressed mice. In contrast, alpha-helical CRF at 0.38 and 0.75 nmol/mouse increased the time in SART-stressed mice. Both immobility time in the forced swimming test and time spent in open arms in the elevated plus-maze test in unstressed and SART-stressed mice were unaffected by adrenalectomy. These results suggest that CRF plays an important role in anxiety-like behavior caused by SART stress.