We have recently reported that repeated systemic treatments of extract from Corydalis yanhusuo alleviate neuropathic pain and levo-tetrahydropalmatine (l-THP) is one of active components from Corydalis. We designed this study to investigate antinociceptive effect of l-THP in acute and chronic pain models and related mechanism within the spinal cord. We found that intraperitoneal pretreatment with l-THP significantly inhibited the second phase of formalin-induced pain behavior. In addition, intrathecal as well as intraperitoneal pretreatment with l-THP reduced the mechanical allodynia (MA) induced by direct activation of sigma-1 receptor (Sig-1). In chronic constriction injury mice, these treatments remarkably suppressed the increase in MA and spinal phosphorylation of the NMDA receptor NR1 subunit expression on day 7 after surgery. Intrathecal treatment with l-THP combined with the Sig-1R antagonist, BD1047 synergistically blocked MA suggesting that l-THP modulates spinal Sig-1R activation. CatWalk gait analysis also supported that antinociceptive effect of l-THP as demonstrated by restoration of percentages of print area and single stance. Meanwhile, intrathecal pretreatment with naloxone, non-selective opioid receptor antagonist, did not affect the effect of l-THP. In conclusion, these results demonstrate that l-THP possesses antinociceptive effects through spinal Sig-1R mechanism and may be a useful analgesic in the management of neuropathic pain.

This study was designed to determine the antinociceptive effect and related neuronal mechanism of electroacupuncture (EA) on paclitaxel (PTX)-induced neuropathic pain in mice. PTX (4 mg/kg, i.p.) was administered once a day for 5 consecutive days to induce neuropathic pain. EA stimulation (2 mA, 2 Hz, 30 min) was applied at the ST36 acupoint bilaterally once in every 2 days. Repeated EA stimulation significantly attenuated PTX-induced mechanical allodynia and thermal hyperalgesia. In a separate set of experiment, the antinociceptive effect of a single EA stimulation 8 days after PTX treatment was reduced by intrathecal pretreatment with naloxone (opioid receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or propranolol (beta-adrenoceptor antagonist), but not prazosin (alpha1-adrenoceptor antagonist). Moreover, EA remarkably suppressed the PTX-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn, and intrathecal pretreatment of naloxone, idazoxan (IDA) or propranolol blocked the effect of EA. In conclusion, EA stimulation at the ST36 acupoint significantly diminished PTX-induced neuropathic pain in mice via the mediation of spinal opioid receptor, alpha2- and beta-adrenoceptors.

Peripheral or central nerve injury often leads to neuropathic pain. Although ketamine and pregabalin are first line options for the treatment of neuropathic pain, their clinical application is limited due to side effects such as sedation, dizziness and somnolence. We designed this study to determine whether the intrathecal (i.t.) co-treatment with ketamine and pregabalin at sub-effective low doses would elicit a sufficient pain relief without producing side effect in a neuropathic pain mouse model. At day 7 after chronic constriction injury (CCI) of sciatic nerve, dose dependent effects of i.t. ketamine (3, 10, 30, 100 µg) or i.t. pregabalin (10, 30, 100 µg) on mechanical allodynia and thermal hyperalgesia were measured. For combination treatment, 3 or 10 µg of ketamine and 30 µg of pregabalin were selected because these doses of drugs were not effective on neuropathic pain. Interestingly, combined i.t. treatment groups (ketamine 3 µg+pregabalin 30 µg and ketamine 10 µg+pregabalin 30 µg) produced strong analgesia on neuropathic pain although these doses of ketamine and pregabalin alone are not effective. Moreover, rota rod test revealed that normal motor function was not affected by combined treatment while i.t. ketamine at doses above 10 µg showed a significant motor dysfunction. Results of this study suggested that i.t. co-treatment with ketamine and pregabalin at sub-effect low doses may be a useful therapeutic method for the treatment of neuropathic pain patients.Key words neuropathic pain; intrathecal; combination drug therapy; ketamine; pregabalin; mouse Peripheral or central nerve injury by a cancer, trauma, and/ or metabolic disease condition may evoke chronic neuropathic pain which is characterized by a presence of spontaneous pain (pain sensation without any stimulation), allodynia (pain sensation by a non-noxious stimulation), and hyperalgesia (enhanced pain by a noxious stimulation).1-4) The development and maintenance of neuropathic pain have been known to be closely associated with a variety of pathophysiologic changes, including peripheral and central sensitization. 5,6) At the periphery, up-regulation of α2δ subunit of voltagedependent calcium channel in the dorsal root ganglion correlates with the onset of tactile allodynia in spinal nerve-injured rats.7) Recently marketed drugs, gabapentin and pregabalin are used as a first line option for the treatment of neuropathic pain and its pain relief effect is induced by a blockade of Ca 2+ influx of sensory neuron via binding with α2δ subunit of Ca 2+ channel. 8,9) In addition, these treatments inhibit the release of excitatory neurotransmitters including glutamate, substance P and calcitonin gene-related peptide at a rodent spinal cord. [10][11][12][13] However, use of α2δ subunit Ca 2+ channel blockers has been limited since relatively higher dose is needed to produce a sufficient pain relief and several adverse effects such as dizziness and somnolence have been reported. 14,15) The N-methyl-d-aspartate (NMDA) receptor is highly expressed in the cen...

In this study, we examined the antinociceptive effect of Cyperi rhizoma (CR) and Corydalis tuber (CT) extracts using a chronic constriction injury-induced neuropathic pain rat model. After the ligation of sciatic nerve, neuropathic pain behavior such as mechanical allodynia and thermal hyperalgesia were rapidly induced and maintained for 1 month. Repeated treatment of CR or CT (per oral, 10 or 30 mg/kg, twice a day) was performed either in induction (day 0∼ 5) or maintenance (day 14∼ 19) period of neuropathic pain state. Treatment of CR or CT at doses of 30 mg/kg in the induction and maintenance periods significantly decreased the nerve injury-induced mechanical allodynia. In addition, CR and CT at doses of 10 or 30 mg/kg alleviated thermal heat hyperalgesia when they were treated in the maintenance period. Finally, CR or CT (30 mg/kg) treated during the induction period remarkably reduced the nerve injury-induced phosphorylation of NMDA receptor NR1 subunit (pNR1) in the spinal dorsal horn. Results of this study suggest that extracts from CR and CT may be useful to alleviate neuropathic pain.

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