Antinociceptive Profile of Levo-tetrahydropalmatine in Acute and Chronic Pain Mice Models: Role of spinal sigma-1 receptor.

Dong-Wook Kang,Jin Bong Park,Hyun-Woo Kim,Jang-Hern Lee,Ji-Young Moon,Suk-Yun Kang,Jae-Gyun Choi,Yeonhee Ryu

doi:10.1038/srep37850

Abstract

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.

Highlights

Chronic pain is a major health problem and one of the most frequent reasons for seeking medical attention[1]
We have previously reported that the direct activation of spinal Sig-1Rs using intrathecal (i.t) injection of agonist increases the response to peripheral mechanical stimuli, which is related with protein kinase C (PKC)- and PKA-dependent Phosphorylation of the NR1 subunit (pNR1) in the spinal cord dorsal horn[20,21]
Discussion l-THP has been used clinically in china for more than 40 years as an analgesic drug for the treatment of mild or moderate pain. It has been reported the analgesic effect of systemic administration with l-THP in several pain models

Summary

Introduction

Chronic pain is a major health problem and one of the most frequent reasons for seeking medical attention[1]. Phosphorylation of the NR1 subunit (pNR1) at protein kinase C (PKC) and protein kinase A(PKA)-dependent sites has been demonstrated to play an important role in enhancement of NMDAR activity related to pain transmission in the spinal cord[14,15]. We have previously reported that the direct activation of spinal Sig-1Rs using intrathecal (i.t) injection of agonist increases the response to peripheral mechanical stimuli, which is related with PKC- and PKA-dependent pNR1 in the spinal cord dorsal horn[20,21]. The antinociceptive effect of Sig-1R antagonist is similar to that of CT treatment as previously reported In this regard, we hypothesized that l-THP may have anti-hyperalgesic effect through the spinal Sig-1R modulation in acute and chronic pain model in mice. The present study was designed to examine: (1) whether l-THP pretreatment reduces formalin-induced pain behavior (2) the relationship with spinal Sig-1R (3) whether i.t treatment with l-THP affects MA and gate parameters in CCI mice using both with von Frey filaments and CatWalk automated quantitative gait analysis and (4) whether i.t treatment with l-THP reduces increase in spinal pNR1 expression in CCI mice

Methods

Results

Conclusion