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In order to explore the peripheral microcirculation and to obtain an outline of autonomic innervation in SART (specific alternation of rhythm in temperature)-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 SART 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 SART stress after left-cervical vagotomy, SART stress failed to elicit any decrease in gastric blood flow. In SART-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.

In SART-stressed rats regarded as pathologically diseased model animals with vagotonic-type autonomic imbalance, a decrease of total acetylcholine (T-ACh) content and enhancements of choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities were recognized in the basal ganglia and hypothalamus. In contrast, in the duodenum, an increase in T-ACh content and a decrease in AChE activity were found, while CAT activity showed no change. These findings suggest that in both brain areas of basal ganglia and hypothalamus in SART-stressed rats, ACh neurons may be activated.

An attempt was made to investigate the preventive effects of 20S-prosapogenin (20S-PG), a partial hydrolyzate of diol saponins isolated from Panax ginseng, on changes of peripheral tissue blood flow in diseased model animals with vagotonic-type autonomic imbalance [SART (specific alternation of rhythm in temperature)-stressed (repeated cold-stressed) mice developed by us], and sympathicotonic-type stressed mice [restraint and water immersion-stressed (R WIS) mice], using the hydrogen clearance method. Decreases in gastric blood flow in both body and pyloric regions of the stomach and increases in dermal blood in both the shoulder and lumbar region in SART-stressed mice were prevented to a considerable extent by daily treatments with 20S-PG, 2.5-10 mg/kg/d. Similarly, the marked decrease in gastric blood flow following R WIS loading was significantly blocked by 10 mg/kg/d of 20S-PG. 20S-PG had a minor preventive effect on decreases in hepatic and dermal blood flow in R WIS mice. The preventive effect of 20S-PG on changes in tissue blood flow, recognized in model animals with autonomic imbalance not only in the vagotonic state but also in the sympathicotonic state, is therefore regarded with considerable interest and may provide a clue to explain the pharmacological action of ginseng.

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.

1 The catecholamine levels in the brains of SART (specific alternation of rhythm in temperature)-stressed (repeated cold-stressed) rats with vagotonic-type dysautonomia, were examined by high performance liquid chromatography with electrochemical detection techniques. 2 The cerebral cortex, hypothalamus and hippocampus of the SART-stressed rats had increased levels of noradrenaline. All brain areas examined showed increased levels of dopamine. 3 These increased catecholamine levels were still maintained by day 10 of SART stress. 4 Among brain areas examined, the hypothalamus showed most rapid change. 5 Cold-stressed rats showed increased noradrenaline levels only in the basal ganglia and dopamine levels in the hippocampus. 6 Rats suffering from restraint and water immersion stress showed decreased noradrenaline levels and increased dopamine levels. 7 These results suggest that SART-stressed animals are in a disease state differing from that of other so-called stressed animals, and changes in the hypothalamus give rise to the various symptoms in SART-stressed animals.

We examined the effects of intraplantar (i.pl.) administration of NaHS, an H2S donor, known to cause T-type Ca2+ channel (T-channel)-dependent mechanical hyperalgesia, on responsiveness to electric stimulation with 5, 250 and 2000 Hz sine waves (SW) that selectively excites C, Aδ and Aβ fibers, respectively. NaHS, given i.pl., caused behavioral hypersensitivity to SW stimulation at 5 Hz, but not 250 or 2000 Hz, in rats. NaHS also enhanced phosphorylation of spinal ERK following 5 Hz SW stimulation. Three distinct T-channel blockers abolished the NaHS-induced behavioral hypersensitivity to 5 Hz SW stimulation. Thus, H2S selectively sensitizes C-fiber nociceptors via T-channels.

Ca v 3.2 T-type Ca 2+ channels targeted by H 2 S, a gasotransmitter, participate in cyclophosphamide-induced cystitis and bladder pain. Given that zinc selectively inhibits Ca v 3.2 among T-channel isoforms and also exhibits antioxidant activity, we examined whether polaprezinc (zinc- l -carnosine), a medicine for peptic ulcer treatment and zinc supplementation, reveals preventive or therapeutic effects on bladder inflammation and/or pain in the mouse with cyclophosphamide-induced cystitis, a model for interstitial cystitis. Systemic administration of cyclophosphamide caused cystitis-related symptoms including increased bladder weight and vascular permeability, and histological signs of bladder edema, accompanied by bladder pain-like nociceptive behavior/referred hyperalgesia. All these symptoms were significantly attenuated by oral preadministration of polaprezinc at 400 mg/kg. The same dose of polaprezinc also prevented the increased malondialdehyde level, an indicator of lipid peroxidation, and protein upregulation of cystathionine-γ-lyase, an H 2 S-generating enzyme, but not occludin, a tight junction-related membrane protein, in the bladder tissue of cyclophosphamide-treated mice. Oral posttreatment with polaprezinc at 30–100 mg/kg reversed the nociceptive behavior/referred hyperalgesia in a dose-dependent manner without affecting the increased bladder weight. Together, our data show that zinc supplementation with polaprezinc prevents the cyclophosphamide-induced cystitis probably through the antioxidant activity, and, like T-channel blockers, reverses the established cystitis-related bladder pain in mice, suggesting novel therapeutic usefulness of polaprezinc.

As part of an investigation on the behavioral characteristics of SART-stressed animals, an animal model of autonomic imbalance, the open-field behavior of SART-stressed (repeated cold-stressed) rats was studied and compared with that of rats exposed to other types of stress. In addition, the effects of several drugs on it were also studied. As compared with normal rats, SART-stressed rats exhibited increased locomotor activity, rearing and center-field penetration, together with decreased grooming and increased defecation, whereas they showed no significant changes in spontaneous movements in the daytime as measured by an Animex activity meter. These behavioral abnormalities were remarkably different from those due to 1-hr cold, 48-hr cold and repeated restraint stresses. These abnormal forms of open-field behavior due to SART stress were considerably inhibited by chlorpromazine, imipramine and neurotropin at doses having no corresponding influence on normal rats; and they were partially inhibited by alprazolam, diazepam and carpipramine at doses exerting considerable influence on normal rats. The above results show that SART-stressed rats exhibit open-field behavioral abnormalities that are different from those of rats exposed to other types of stress. Such abnormalities include excessive activity, which is considered to be caused by excessive emotionality.

In SART-stressed (repeated cold-stressed) rats, shuttle-avoidance response was examined. The rats exposed to SART stress prior to training showed a high avoidance rate and no change in the intertrial response. Upon exposure to SART stress after completion of learning, the rats showed no changes in the avoidance rate and an increase in the intertrial response in the retention test. These results are in contrast to the previous observations of passive avoidance response, and the abnormal behavior in such animals may be based on excessive emotionality and/or hyperreactivity rather than alterations in the process of learning and memory.

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.

Clinical and immunohistochemical evidence suggests the possible significance of electrical stimulation of the secondary somatosensory cortex (S-II) as an analgesic therapy. The aim of the present study was to gain behavioral evidence for S-II stimulation-induced antinociception in conscious rats and to evaluate if the evoked antinociception can be potentiated by the neuronal NO synthase inhibitor 7-nitro-indazole. S-II stimulation produced a weak antinociception in the formalin-induced nociception test, but not in the thermal or mechanical nociception tests. This effect was remarkably potentiated by systemic administration of 7-nitro-indazole at a small dose that had no effect by itself. Thus, our data provide behavioral evidence for S-II stimulation-induced analgesia and may also predict a novel therapeutic strategy in combination with NO Synthase inhibitors.