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A novel α-conopeptide Eu1.6 inhibits N-type (CaV2.2) calcium channels and exhibits potent analgesic activity

Journal Article


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Abstract


  • We here describe a novel α-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong anti-nociceptive activity by an unexpected mechanism of action. Unlike other α-conopeptides that largely target nicotinic acetylcholine receptors (nAChRs), Eu1.6 displayed only weak inhibitory activity at the α3β4 and α7 nAChR subtypes and TTX-resistant sodium channels, and no activity at TTX-sensitive sodium channels in rat dorsal root ganglion (DRG) neurons, or opiate receptors, VR1, KCNQ1, L- and T-type calcium channels expressed in HEK293 cells. However, Eu1.6 inhibited high voltage-activated N-type calcium channel currents in isolated mouse DRG neurons which was independent of GABAB receptor activation. In HEK293 cells expressing CaV2.2 channels alone, Eu1.6 reversibly inhibited depolarization-activated Ba2+ currents in a voltage- and state-dependent manner. Inhibition of CaV2.2 by Eu1.6 was concentration-dependent (IC50 ~1 nM). Significantly, systemic administration of Eu1.6 at doses of 2.5–5.0 μg/kg exhibited potent analgesic activities in rat partial sciatic nerve injury and chronic constriction injury pain models. Furthermore, Eu1.6 had no significant side-effect on spontaneous locomotor activity, cardiac and respiratory function, and drug dependence in mice. These findings suggest α-conopeptide Eu1.6 is a potent analgesic for the treatment of neuropathic and chronic pain and opens a novel option for future analgesic drug design.

Authors


  •   Liu, Zhuguo (external author)
  •   Bartels, Peter (external author)
  •   Sadeghi, Mahsa (external author)
  •   Du, Tianpeng (external author)
  •   Dai, Qing (external author)
  •   Zhu, Cui (external author)
  •   Yu, Shuo (external author)
  •   Wang, Shuo (external author)
  •   Dong, Mingxin (external author)
  •   Sun, Ting (external author)
  •   Guo, Jiabin (external author)
  •   Peng, Shuangqing (external author)
  •   Jiang, Ling (external author)
  •   Adams, David J.
  •   Dai, Qiuyun (external author)

Publication Date


  • 2018

Citation


  • Liu, Z., Bartels, P., Sadeghi, M., Du, T., Dai, Q., Zhu, C., Yu, S., Wang, S., Dong, M., Sun, T., Guo, J., Peng, S., Jiang, L., Adams, D. J. & Dai, Q. (2018). A novel α-conopeptide Eu1.6 inhibits N-type (CaV2.2) calcium channels and exhibits potent analgesic activity. Scientific Reports, 8 1004-1-1004-13.

Scopus Eid


  • 2-s2.0-85041620518

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2231&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1204

Start Page


  • 1004-1

End Page


  • 1004-13

Volume


  • 8

Place Of Publication


  • United Kingdom

Abstract


  • We here describe a novel α-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong anti-nociceptive activity by an unexpected mechanism of action. Unlike other α-conopeptides that largely target nicotinic acetylcholine receptors (nAChRs), Eu1.6 displayed only weak inhibitory activity at the α3β4 and α7 nAChR subtypes and TTX-resistant sodium channels, and no activity at TTX-sensitive sodium channels in rat dorsal root ganglion (DRG) neurons, or opiate receptors, VR1, KCNQ1, L- and T-type calcium channels expressed in HEK293 cells. However, Eu1.6 inhibited high voltage-activated N-type calcium channel currents in isolated mouse DRG neurons which was independent of GABAB receptor activation. In HEK293 cells expressing CaV2.2 channels alone, Eu1.6 reversibly inhibited depolarization-activated Ba2+ currents in a voltage- and state-dependent manner. Inhibition of CaV2.2 by Eu1.6 was concentration-dependent (IC50 ~1 nM). Significantly, systemic administration of Eu1.6 at doses of 2.5–5.0 μg/kg exhibited potent analgesic activities in rat partial sciatic nerve injury and chronic constriction injury pain models. Furthermore, Eu1.6 had no significant side-effect on spontaneous locomotor activity, cardiac and respiratory function, and drug dependence in mice. These findings suggest α-conopeptide Eu1.6 is a potent analgesic for the treatment of neuropathic and chronic pain and opens a novel option for future analgesic drug design.

Authors


  •   Liu, Zhuguo (external author)
  •   Bartels, Peter (external author)
  •   Sadeghi, Mahsa (external author)
  •   Du, Tianpeng (external author)
  •   Dai, Qing (external author)
  •   Zhu, Cui (external author)
  •   Yu, Shuo (external author)
  •   Wang, Shuo (external author)
  •   Dong, Mingxin (external author)
  •   Sun, Ting (external author)
  •   Guo, Jiabin (external author)
  •   Peng, Shuangqing (external author)
  •   Jiang, Ling (external author)
  •   Adams, David J.
  •   Dai, Qiuyun (external author)

Publication Date


  • 2018

Citation


  • Liu, Z., Bartels, P., Sadeghi, M., Du, T., Dai, Q., Zhu, C., Yu, S., Wang, S., Dong, M., Sun, T., Guo, J., Peng, S., Jiang, L., Adams, D. J. & Dai, Q. (2018). A novel α-conopeptide Eu1.6 inhibits N-type (CaV2.2) calcium channels and exhibits potent analgesic activity. Scientific Reports, 8 1004-1-1004-13.

Scopus Eid


  • 2-s2.0-85041620518

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2231&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1204

Start Page


  • 1004-1

End Page


  • 1004-13

Volume


  • 8

Place Of Publication


  • United Kingdom