This study was conducted to clarify the analgesic effect of toad cake and toad-cake-containing herbal drugs.
We counted the writhing response of mice after the intraperitoneal administration of acetic acid as a nociceptive pain model and the withdrawal response after the plantar surface stimulation of the hind paw induced by partial sciatic nerve ligation of the mice as a neuropathic pain model to investigate the analgesic effect of toad cake and toad-cake-containing herbal drugs. A co-treatment study with serotonin biosynthesis inhibitory drug 4-chloro-
Analgesic effects in a mouse model of nociceptive pain and neuropathic pain were shown by oral administration of toad cake and toad-cake-containing herbal drugs. The effects of toad cake and toad-cake-containing herbal drugs disappeared upon co-treatment with PCPA, but not with AMPT or naloxone in the nociceptive pain model; the analgesic effect of toad-cake-containing herbal drugs also disappeared upon co-treatment with PCPA in the neuropathic pain model.
Toad cake and toad-cake-containing herbal drugs have potential for the treatments of nociceptive pain and of neuropathic pain, such as post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and postoperative or posttraumatic pain, by activation of the central serotonin nervous system.
Pain is a useful protective mechanism that warns the body of danger and is also important as a signal of organic change. However, in many cases, pain that develops pathologically is not useful and reduces the quality of life (QOL). Pain accompanying organic change can be divided into nociceptive pain and neuropathic pain [
Toad cake (Ch’an Su) is the dried venom of the toad
Five- or six-week-old male ddY mice were obtained from Japan SLC (Shizuoka, Japan) or JLA (Tokyo, Japan) and were used at six or seven weeks of age after an acclimatization period. All animals were maintained in a room with controlled temperature (22 ± 1℃) and humidity (55 ± 10%), along with a 12-hour light-dark cycle, and were allowed free access to standard lab chow and tap water. The experimental protocol was approved by the Animal Care and Use Committee of Kyushin Pharmaceutical Co., Ltd. Furthermore, the study protocol complied with the laws and notifications of the Japanese government prior to commencement of the study.
Two kinds of formulations of
Test drugs (KY, KYR, toad cake, fluvoxamine and
The writhing responses of the mice after the intraperitoneal administration of acetic acid [
The sciatic nerve ligation model (Seltzer-model [
Data were presented as means ± standard errors (SEs). The significances of the differences in the data were estimated using the one-way analysis of variance (ANOVA), followed by the Dunnett’s multiple range test.
A significant reduction of the writhing response was shown by oral administration of KY (9 mg/kg and 27 mg/ kg), KYR (27 mg/kg), toad cake (1.5 mg/kg) or
In the mice whose sciatic nerve had been partially ligated, the frequency of hind-paw withdrawal response when using a filament stimulus of 0.166- or 0.407-g force was increased on the 4th and the 7th day of the test drug’s administration. This increase in the frequency of hind-paw withdrawal response was reduced by oral administration of KY (27 mg/kg/day), KYR (27 mg/kg/day), toad cake (1.5 mg/kg/day) or fluvoxamine maleate (30 mg/kg/day) (Fig. 3). In the co-treatment study with PCPA, the analgesic effect of KY and fluvoxamine maleate disappeared (Fig. 4).
Toad cake, KY and KYR, when administered orally, showed analgesic effects in the nociceptive pain and the neuropathic pain. Telocinobufagin, one of the main components of toad cake, has also been reported to show analgesic effects in nociceptive pain and neuropathic pain models [
In the co-treatment studies with the serotonin biosynthesis inhibitory drug PCPA, the catecholamine biosynthesis inhibitory drug AMPT or the opioid receptor antagonist naloxone hydrochloride, the analgesic effects of toad cake, KY and KYR disappeared upon co-treatment with PCPA, but not with AMPT and naloxone in the nociceptive pain model, and the analgesic effect of KY also disappeared upon co-treatment with PCPA in the neuropathic pain model. In our previous studies [
In our study, analgesic effects were observed significantly with 9 mg/kg KY (27 mg/kg KYR) in the nociceptive pain model and with 27 mg/kg KY and KYR in the neuropathic pain model. These doses were about 6 or 18 times the human daily dose (90 mg/day) as an OTC drug, but there is a report stating that the drug sensitivity of mice is 1/12 that of humans based on the body surface area per weight [17]. Therefore, daily doses of KY and KYR may have an analgesic effect in humans.
In summary, in addition to nociceptive pain, toad cake and toad-cake-containing herbal drugs (KY, KYR) have analgesic effects in a mouse model of neuropathic pain, which suggests that these drugs have potential for the treatment of conditions such as post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and postoperative or posttraumatic pain. However, more detailed fundamental and clinical studies are needed.
This study was conducted to clarify the analgesic effect of toad cake and toad-cake-containing herbal drugs. Toad cake and toad-cake-containing herbal drugs have analgesic effects in a mouse model of nociceptive pain and neuropathic pain by activation of the central serotonin nervous system, which suggests that these drugs have potential for the treatment of conditions such as post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and postoperative or posttraumatic pain.