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Dermorphin [D-Arg2, Lys4] (1-4) amide inhibits below-level heat hypersensitivity in mice after contusive thoracic spinal cord injury

Liu, Shuguanga,b; Huang, Qianb; He, Shaoqiub; Chen, Zhiyongb; Gao, Xinyanb,c; Ma, Danxub,d; Duan, Wanrub,e; Ford, Neilb; Yang, Feib,f; Chen, Xuemingg; Raja, Srinivasa N.b; Hao, Dingjuna; Guan, Yunb,h,*

doi: 10.1097/j.pain.0000000000001671
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Opioid use for chronic pain is limited by severe central adverse effects. We examined whether activating mu-opioid receptors (MORs) in the peripheral nervous system attenuates spinal cord injury (SCI) pain-like behavior in mice. We produced a contusive SCI at the T10 vertebral level and examined motor and sensory dysfunction for 6 weeks. At 6 weeks, we tested the effect of subcutaneous (s.c.) injection of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripherally acting MOR-preferring agonist, on mechanical and heat hypersensitivity. Basso mouse scale score was significantly decreased after SCI, and mice showed hypersensitivity to mechanical and heat stimulation at the hind paw beginning at 2 weeks, as indicated by increased paw withdrawal frequency to mechanical stimulation and decreased paw withdrawal latency to heat stimulation. In wild-type SCI mice, DALDA (1 mg/kg, s.c.) attenuated heat but not mechanical hypersensitivity. The effect was blocked by pretreatment with an intraperitoneal injection of methylnaltrexone (5 mg/kg), a peripherally restricted opioid receptor antagonist, and was also diminished in Pirt-MOR conditional knockout mice. DALDA did not adversely affect exploratory activity or induced preference to drug treatment in SCI mice. In vivo calcium imaging showed that DALDA (1, 10 mg/kg, s.c.) inhibited responses of small dorsal root ganglion neurons to noxious heat stimulation in Pirt-GCaMP6s mice after SCI. Western blot analysis showed upregulation of MOR in the lumbar spinal cord and sciatic nerves at 6 weeks after SCI. Our findings suggest that peripherally acting MOR agonist may inhibit heat hypersensitivity below the injury level with minimal adverse effects.

This study shows upregulations of mu-opioid receptor expression in the lumbar spinal cord and sciatic nerves after thoracic spinal cord injury and inhibition of heat hypersensitivity by DALDA in mice.

aDepartment of Orthopedics, Honghui Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China

bDepartment of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United States

cInstitute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China

dDepartment of Anesthesiology, Chaoyang Hospital, Capital Medical University, Beijing, China

eDepartment of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China

fDepartment of Neurobiology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China

gDepartment of Orthopedics, Luhe Hospital, Capital Medical University, Beijing, China

hDepartment of Neurological Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, United States

*Corresponding author. Address: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States. Tel.: 410-502-5511; fax: 410-614-2109. E-mail address: yguan1@jhmi.edu (Y. Guan).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

S. Liu and Q. Huang contributed equally to this work.

© 2019 International Association for the Study of Pain
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