Yokukansan (Kampo medicinal formula) prevents the development of morphine tolerance by inhibiting the secretion of orexin A

Abstract

BackgroundYokukansan (YKS), a traditional herbal (Kampo) medicine consisting of seven herbs, is effective in the treatment of pain disorders, such as headache, postherpetic neuralgia, fibromyalgia, and trigeminal neuralgia, and we have previously shown it to be effective against morphine analgesic tolerance in rats. It has been reported that orexin receptor antagonists prevent the development of morphine tolerance and that YKS inhibits the secretion of orexin A in the hypothalamus. This study examined whether the inhibition of the secretion of orexin A by YKS is one mechanism underlying its effect against morphine analgesic tolerance.MethodsMale Wistar rats were administered a subcutaneous injection of morphine hydrochloride (10 mg/kg/day) for 5 days. One group was preadministered YKS, starting 3 days before the morphine. The withdrawal latency following thermal stimulation was measured daily using a hot plate test. On day 5, the levels of orexin A in the plasma and the midbrain were measured, and the appearance of activated astrocytes in the midbrain was examined by immunofluorescence staining.ResultsThe preadministration of YKS prevented the development of morphine tolerance. The repeated administration of morphine significantly increased the plasma and midbrain levels of orexin A and the activation of astrocytes. These increases were significantly inhibited by the preadministration of YKS.ConclusionThese results suggest that the preadministration of YKS attenuated the development of antinociceptive morphine tolerance and that the inhibition of orexin A secretion may be one mechanism underlying this phenomenon.

Effectiveness of the traditional Japanese Kampo medicine Yokukansan for chronic migraine

“…It is highly likely that the neuropeptide serotonin, its receptors (particularly 5-HT 1B/1D receptors widely distributed in cerebral vasculature), and the vasodilator calcitonin gene-related peptide are involved. Nevertheless, the mechanism of action of Yokukansan remains unclear, although the following actions have been reported: (1) suppression of neuronal excitation in the glutamatergic system through suppression of glutamate release action which affects N-methyl-D-aspartic acid receptors, activation of glutamate transporters, adjustment of glutamate uptake, and suppression of increases in the extracellular glutamate level [19–21] ; (2) increased extracellular serotonin level in the serotonergic central nervous system through partial agonist effect on 5-HT 1A receptors and downregulation of 5-HT 1A receptors [22–24] ; (3) inhibition of orexin A secretion [25] ; and (4) anti-inflammatory effects. [26,27]…”

Analgesic Efficacy of a Combination of Fentanyl and a Japanese Herbal Medicine “Yokukansan” in Rats with Acute Inflammatory Pain

“…YKS has an ameliorative effect on glutamate clearance in astrocytes and an antagonistic action at the NMDA receptor [ 35 , 36 , 37 ]. Additionally, we previously reported that administration of YKS attenuated the development of antinociceptive morphine tolerance, and that suppression of glial cell activation in the spinal cord and mesencephalon may be one mechanism underlying this phenomenon [ 33 , 34 ]. These mechanisms are also thought to contribute to the preventative effect of YKS on the development of FIH.…”

“…This dose was chosen on the basis of effective doses of YKS in our previous study [ 33 ]. Previous studies have indicated that pre-administration of YKS may inhibit development of antinociceptive tolerance to morphine [ 33 , 34 , 43 ]. Thus, in this study, YKS administration was started 7 days before fentanyl injection.…”

“…Studies have demonstrated antinociceptive effects of YKS in animal models with chronic neuropathic and inflammatory pain [ 29 , 30 , 31 , 32 ]. We previously reported that pre-administration of YKS attenuated the development of antinociceptive morphine tolerance and that suppression of glial cell activation may be one mechanism underlying this phenomenon [ 33 , 34 ]. YKS is also known to have an ameliorative effect on glutamate clearance in astrocytes and an antagonistic action at the NMDA receptor [ 35 , 36 , 37 ].…”

Effect of hangebyakujutsutemmato on pregabalin‐induced dizziness in a rat model of neuropathic pain

“…There have been no previous studies on the treatment of rats with HBT. Based on previous studies involving kampo medicine, a dosage of 1 g/kg/day was used, which enabled us to demonstrate the effect of HBT on pregabalin‐induced dizziness. There is a need for further studies on the dose‐dependent effect of HBT.…”