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Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury.

ABSTRACT: Gene therapy for neuropathic pain requires efficient gene delivery to both central and peripheral nervous systems. We previously showed that an adenoassociated virus serotype 9 (AAV9) vector expressing short-hairpin RNA (shRNA) could suppress target molecule expression in the dorsal root ganglia (DRG) and spinal cord upon intrathecal injection. To evaluate the therapeutic potential of this approach, we constructed an AAV9 vector encoding shRNA against vanilloid receptor 1 (TRPV1), which is an important target gene for acute pain, but its role in chronic neuropathic pain remains unclear. We intrathecally injected it into the subarachnoid space at the upper lumbar spine of mice 3 weeks after spared nerve injury (SNI). Delivered shTRPV1 effectively suppressed mRNA and protein expression of TRPV1 in the DRG and spinal cord, and it attenuated nerve injury-induced thermal allodynia 10-28 days after treatment. Our study provides important evidence for the contribution of TRPV1 to thermal hypersensitivity in neuropathic pain and thus establishes intrathecal AAV9-mediated gene delivery as an investigative and potentially therapeutic platform for the nervous system.

SUBMITTER: Hirai T

PROVIDER: S-EPMC3916042 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury.

Hirai Takashi T Enomoto Mitsuhiro M Kaburagi Hidetoshi H Sotome Shinichi S Yoshida-Tanaka Kie K Ukegawa Madoka M Kuwahara Hiroya H Yamamoto Mariko M Tajiri Mio M Miyata Haruka H Hirai Yukihiko Y Tominaga Makoto M Shinomiya Kenichi K Mizusawa Hidehiro H Okawa Atsushi A Yokota Takanori T

Molecular therapy : the journal of the American Society of Gene Therapy 20131028 2

Gene therapy for neuropathic pain requires efficient gene delivery to both central and peripheral nervous systems. We previously showed that an adenoassociated virus serotype 9 (AAV9) vector expressing short-hairpin RNA (shRNA) could suppress target molecule expression in the dorsal root ganglia (DRG) and spinal cord upon intrathecal injection. To evaluate the therapeutic potential of this approach, we constructed an AAV9 vector encoding shRNA against vanilloid receptor 1 (TRPV1), which is an im ...[more]

PMID: 24322332

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Project description:IntroductionThe aim of this study was to observe the effect of stress caused by neuropathic pain on serum cortisol concentration and expression of 11β-hydroxysteroid dehydrogenase type I enzyme (11βHSD1) in spinal cord and dorsal root ganglions (DRG) and investigate the role and mechanism of curcumin in the neuropathic pain of stressful rats. Neuropathic pain is a prevalent disease that greatly impairs the patients' quality of life. A lack of the understanding of its etiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect of curcumin and its effect on expression of 11β-hydroxysteroid dehydrogenase type I enzyme (11βHSD1) in spinal dorsal horn and DRG in chronic constriction injury (CCI) mode of neuropathic pain of rats.MethodsSeventy-two male Sprague-Dawley rats were randomized into four groups with 18 rats in each: sham operation group (Sham), chronic constrictive injury group (CCI), solvent contrast group (SC), and curcumin-treated group (Cur100). Curcumin, 100 mg/kg/day intraperitoneal, was given for 14 days starting from the first day after operation in the Cur100 group. Paw thermal withdrawal latency (PTWL) and paw mechanical withdrawal threshold (PMWT) of rats were measured 2 days pre-operative, and 1, 3, 5, 7, 10, and 14 days post-operative. The animals were deeply anesthetized and blood was taken from the heart, the lumbar segment (L4, 5) of the spinal cord and DRG were dissected out and homogenized. The change of cortisol was measured by enzyme-linked immunosorbent assay and the change of 11βHSD1 expression was determined by immunochemistry and Western blot.ResultsCompared with sham group, PTWL and PMWT significantly decrease after operation in the CCI group; serum cortisol concentration was significantly increased and the expression of 11βHSD1 was significantly increased in the CCI group. Comparing with CCI group, the PMWT and PTWL were increased and the serum cortisol concentration was decreased and the expression of 11βHSD1 was inhibited in Cur100 group.ConclusionStress caused by neuropathic pain triggers release of cortisol to the blood and expression of 11βHSD1 would increase at the same time. Curcumin could alleviate thermal and mechanical hyperalgesia induced by CCI and inhibit the serum cortisol concentration and expression of 11βHSD1 in the spinal cord and DRG.

Dataset Information

Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury.

Publications

Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury.

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