Abstract-In order to explore the peripheral microcirculation and to obtain an outline of autonomic innervation in SARI (specific alternation of rhythm in temper ature)-stressed (repeated cold-stressed) animals, which are regarded as model animals for clinical vagotonic-type dysautonomia, peripheral tissue blood flow was determined in mice, using the hydrogen clearance method.SART-stressed mice showed a decrease in gastric blood flow, no change in hepatic blood flow and an increase in dermal blood flow. In the mice exposed to the restraint and water immersion stress (RWIS), a type of acute stress, in contrast with SARI stress which is a subacute type, remarkable decreases were observed in gastric, hepatic and dermal blood flows.Changes of both gastric and dermal blood flow in SART stressed mice were dose-dependently prevented and maintained within normal limits by the treatment with Neurotropin, a sedative analgesic which is an extract isolated from vaccinia virus-inoculated and inflamed skin of rabbits. In RWIS loaded mice, Neurotropin exhibited a great preventive effect on changes of blood flow in the stomach, a slight effect in the liver, and no effect in the cutis. When mice were loaded with SARI stress after left-cervical vagotomy, SARI stress failed to elicit any decrease in gastric blood flow. In SARI-stressed mice treated with 6 hydroxydopamine, gastric and dermal blood flows tended to show a further decrease and increase, respectively, over and above the changes caused by SART stress. From these results, it is suggested that SART-stressed mice may have decreased gastric parasympathetic tone, a decrease in sympathetic tone and also other anomalies such as increased tension of the sympathetic cholinergic vasodilator nerves in the cutis.There have been numerous reports that SART (specific alternation of rhythm in temperature) -stressed (repeated cold stressed) animals (1, 2), vagotonic-type model animals (3) for clinical autonomic imbalance, show various physiological changes (3-7). With respect to the circu latory system of SART-stressed animals, several abnormalities (5,6,8,9) such as a continuous lowering of blood pressure (5), sympathicotonic-type ECG (electrocardio gram) (6), increases in blood flow in the abdominal aorta and superior mesenteric artery, and decreased blood flow in the common carotid artery (5), have been previously reported.
1 The mechanism of hyperalgesia observed in SART (repeated cold)-stressed animals (mice and rats) was studied in relation to the autonomic nervous system.2 SART stress reduced the nociceptive threshold previously increased in vagotomized mice, but failed to change the threshold previously decreased in sympathectomized mice.3 The nociceptive threshold previously decreased in SART-stressed mice was elevated by vagotomy, but decreased still more by sympathectomy. 4 Lesion of ventromedial (VMH), anterior (AH) or posterior hypothalamus (PH) prevented decrease in the nociceptive threshold of rats by SART stress, but lesion of the lateral hypothalamus (LH) had no such effect. 5 The nociceptive threshold previously decreased in stressed rats did not change by VMH, AH or PH lesion, but increased by LH lesion. 6 The above findings indicate that hyperalgesia in SART-stressed animals apparently bears little relation to the parasympathetic nervous system, but is associated relatively more with reduced tone in the sympathetic nervous system.
Abstract-Neurotropin, an extract from the inflamed skin of vaccinia virus inoculated rabbits, has been observed clinically to be effective for treating pain in patients with lumbago, SMON and other neuropathies. In the present study, we examined the mechanism of the antinociceptive effect of neurotropin in mice in relation to administration routes, opioids, and noradrenergic or GABAergic drugs , by the tail pressure method. The antinociceptive effects of neurotropin were large when administered by the i.p. and intracisternal (i.cist.) routes, but comparatively small in the case of the intrathecal (i.th.) route. Neurotropin may thus act at the supraspinal level rather than on the spinal cord. The antinociceptive effect of neurotropin was not blocked by naloxone, and no cross-tolerance developed between neurotropin and morphine. The effect of neurotropin was blocked by phentolamine and reserpine, but not by atropine. Its effect was enhanced by GABA, muscimol, aminooxyacetic acid and diaminobutyric acid, but not by baclofen , and blocked by bicuculline methiodide. From these results, the antinociceptive action of neurotropin appears to be non-opioid in nature, and may possible be mediated by the noradrenergic and GABAergic systems, but unrelated to the cholinergic system. Neurotropin, an extract from the inflamed skin of vaccinia virus-inoculated rabbits, has been clinically reported to show analgesic effects in patients with severe pain (1-5) such as that occurring in cases of lumbago, cervicodynia, SMON and various neuropa thies. Thus, neurotropin can be effectively used to treat patients with chronic pain, but not those with acute pain. In animal experi ments, neurotropin has been reported to exert strong antinociceptive effects (6) on hyperalgesia (7, 8) in SART (specific alter nation of rhythm in temperature)-stressed (repeated cold-stressed) mice (9, 10), which show symptoms of vagotonic-type dysau tonomia (11), and in other types of hyper algesic mice (12).However, the mechanism of its analgesic effect has so far not been clarified. In the present study, therefore, the antinociceptive effects of neurotropin on mice were in vestigated in relation to administration route , opioids, and noradrenergic or GABAergic agents.Neurotropin was administered to mice centrally or peripherally. Materials and MethodsMale ddY mice were used. They were housed at 22-24'C under a regime with a constant day-night rhythm and given food and water ad libitum. Normal healthy mice were used in most of the experiments, while in some experiments, SART-stressed mice were employed.For SART stress loading, the mice were kept alternately at 24 °C and 4'C at 1-hr intervals from 9 a.m. to 4 p.m. and then at 4'C from 4 p.m. to 9 a.m. the following morning. This procedure was repeated for 5 consecutive days (9, 10) and then stopped on the morning of the 6th day of stress. The stressed animals were subjected to experi ments 1 hr or more after the cessation of stress.Drugs were administered intracisternally, intrathecally or intraperitoneally.In...
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