Yokukansan Inhibits the Development of Morphine Tolerance by Regulating Presynaptic Proteins in DRG Neurons

Abstract

Opioids, such as morphine, are used in clinical settings for the management of acute and chronic pain. However, long-term use of morphine leads to antinociceptive tolerance and hypersensitivity. The cellular and molecular mechanisms of morphine tolerance seem to be quite complex, with suggestions including internalization of the μ-opioid receptor (MOR), neuroinflammation with activation of microglia and astrocytes, and changes in synaptic function in the central nervous system. Yokukansan (YKS), a traditional Kampo medicine consisting of seven herbs, has been used to treat emotional instability, neurosis, and insomnia. Interestingly, recent studies have begun to reveal the inhibitory effect of YKS on the development of morphine tolerance. In the present study, we determined the effect of YKS on morphine tolerance formation and its mechanisms in a rat model, focusing on the synapses between primary sensory neurons and spinal dorsal horn secondary neurons. We found that morphine tolerance formation was significantly inhibited by YKS (0.3 or 1.0 g/kg/day) preadministration for 7 days. Repeated administration of morphine (10 mg/kg/day) increased the expression of presynaptic proteins, including synaptotagmin I, in the spinal cord, which was suppressed by YKS. Furthermore, these changes in presynaptic protein expression were more pronounced at isolectin B4 (IB4)-positive excitatory synapses around the lamina II of the dorsal horn. These results suggest that YKS suppresses the development of morphine tolerance by inhibiting the enhancement of presynaptic function of dorsal root ganglia neurons projecting to spinal dorsal horn neurons caused by continuous morphine administration.

Analgesic Effect of the Kampo Formula Yokukansan via the Suppression of Substance P in an Experimental Rat Model of Hunner-Type Interstitial Cystitis

“…BoNT/A cleaves synaptosomal-associated protein-25 (SNAP-25), a key component of the SNARE complex [ 30 ]. We previously demonstrated that YKS inhibited neurotransmitter release by suppressing the overexpression of SNAP-25 [ 15 ]. This led us to speculate that YKS may share a mechanism of action like that of BoNTs.…”

“…YKS is a multi-component drug with multiple pharmacological actions [15][16][17][18]. Previous studies have reported its mechanisms of action, including inhibition of glutamate secretion [15], promotion of glutamate uptake by astrocytes [22], antagonism of glutamate N-methyl-D-aspartate (NMDA) receptors [23], agonistic effects on GABA A and 5-HT 1A receptors that inhibit neurotransmission [24,25], and antioxidant properties [26]. In a previous study using the HIC model animal, we reported the involvement of the antioxidant activity [18].…”

“…including fibromyalgia, post-herpetic neuralgia, cancer pain, phantom limb pain, headache, and trigeminal neuralgia [11,12]. Basic studies [13][14][15][16][17] have also suggested that it has effects. However, the effectiveness and mechanisms of action of YKS in HIC have not been firmly established.…”

Conference report: Fourth annual young researcher forum of the Japan Society of Medical and Pharmaceutical Sciences for Traditional Medicine

“…This study aimed to investigate the efficacy of yokukansan in alleviating pain and psychiatric symptoms in patients with cancer undergoing treatment. Yokukansan has inhibitory effects on neuropathic pain and opioid analgesic tolerance in animal experiments and has been reported to improve irritability and sleep disorders in cancer patients [4][5][6]. Although there are reports of its analgesic effects in basic research and case studies, clinical studies validating these effects are scarce.…”