Early hyperbaric oxygen effects on neuropathic pain and nitric oxide synthase isoforms in CCI rats

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Abstract

Neuropathic pain is pain caused by injury or dysfunction in the central and/or peripheral nervous system. Neuropathic pain has a high incidence with a complex mechanism, but effective treatment remains elusive. Hyperbaric oxygen (HBO) therapy has been widely used in the treatment of a variety of neurological diseases. The current study used a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. We observed the effects of early use of 2.5 absolute atmosphere (ATA) HBO on neuropathic pain-related behaviors and the expression of nitric oxide synthase (NOS) isoforms in the spinal dorsal horn. In the CCI group, mechanical withdrawal threshold (MWT) was decreased, Thermal withdrawal latency (TWL) was shortened, and mRNA and protein levels of iNOS and nNOS were significantly increased compared to the sham group. MWT was increased, TWL was enhanced, and iNOS and nNOS levels were significantly decreased in the HBO group compared to the CCI group. There was no change in eNOS levels across all groups. HBO treatment at early stages can improve hyperalgesia.

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Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury.

Joachim Scholz, Daniel Broom, Dong-Ho Youn … (2005)

We show that transsynaptic apoptosis is induced in the superficial dorsal horn (laminas I-III) of the spinal cord by three distinct partial peripheral nerve lesions: spared nerve injury, chronic constriction, and spinal nerve ligation. Ongoing activity in primary afferents of the injured nerve and glutamatergic transmission cause a caspase-dependent degeneration of dorsal horn neurons that is slow in onset and persists for several weeks. Four weeks after spared nerve injury, the cumulative loss of dorsal horn neurons, determined by stereological analysis, is >20%. GABAergic inhibitory interneurons are among the neurons lost, and a marked decrease in inhibitory postsynaptic currents of lamina II neurons coincides with the induction of apoptosis. Blocking apoptosis with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) prevents the loss of GABAergic interneurons and the reduction of inhibitory currents. Partial peripheral nerve injury results in pain-like behavioral changes characterized by hypersensitivity to tactile or cold stimuli. Treatment with zVAD, which has no intrinsic analgesic properties, attenuates this neuropathic pain-like syndrome. Preventing nerve injury-induced apoptosis of dorsal horn neurons by blocking caspase activity maintains inhibitory transmission in lamina II and reduces pain hypersensitivity.

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Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord.

Laurie A Karchewski, Joachim Scholz, Tatsuro Kohno … (2002)

To clarify whether inhibitory transmission in the superficial dorsal horn of the spinal cord is reduced after peripheral nerve injury, we have studied synaptic transmission in lamina II neurons of an isolated adult rat spinal cord slice preparation after complete sciatic nerve transection (SNT), chronic constriction injury (CCI), or spared nerve injury (SNI). Fast excitatory transmission remains intact after all three types of nerve injury. In contrast, primary afferent-evoked IPSCs are substantially reduced in incidence, magnitude, and duration after the two partial nerve injuries, CCI and SNI, but not SNT. Pharmacologically isolated GABA(A) receptor-mediated IPSCs are decreased in the two partial nerve injury models compared with naive animals. An analysis of unitary IPSCs suggests that presynaptic GABA release is reduced after CCI and SNI. Partial nerve injury also decreases dorsal horn levels of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) 65 kDa ipsilateral to the injury and induces neuronal apoptosis, detected by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining in identified neurons. Both of these mechanisms could reduce presynaptic GABA levels and promote a functional loss of GABAergic transmission in the superficial dorsal horn.

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Pharmacological assessments of nitric oxide synthase isoforms and downstream diversity of NO signaling in the maintenance of thermal and mechanical hypersensitivity after peripheral nerve injury in mice.

Mitsuo Tanabe, Yoshinori Nagatani, Kazuya Saitoh … (2009)

Nitric oxide synthase (NOS) isoforms and NO downstream signal pathways involved spinally in the maintenance of thermal and mechanical hypersensitivity were assessed in a mouse model of neuropathic pain developing after partial ligation of the sciatic nerve. Intrathecal injection of the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME), the highly selective neuronal NOS (nNOS) inhibitor N(omega)-propyl-l-arginine and the potent selective inducible NOS (iNOS) inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine hydrochloride (AMT) exerted dose-dependent analgesic effects on thermal and mechanical hypersensitivity, which were assessed by the plantar and von Frey tests, respectively, suggesting that both nNOS and iNOS participate in producing NO to maintain neuropathic pain. Since the selective inhibitor of NO-sensitive guanylyl cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and the guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG) inhibitor Rp-8-pCPT-cGMPS intrathecally exerted dose-dependent analgesic effects on thermal and mechanical hypersensitivity, spinally released NO most likely stimulates the NO-cGMP-PKG pathway. Moreover, the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), a potent superoxide scavenger, reduced thermal and mechanical hypersensitivity when administered intrathecally, suggesting that spinal release of superoxide, which can then react with NO to produce peroxynitrite, also appears to mediate neuropathic pain. Finally, intrathecal injection of phenyl-N-tert-butylnitrone (PBN), a reactive oxygen species (ROS) scavenger, ameliorated thermal and mechanical hypersensitivity, thus further confirming the importance of ROS including NO and superoxide in the maintenance of neuropathic pain. Together, the present results demonstrate that NO, produced presumably via nNOS and iNOS in the spinal cord, mediates the maintenance of neuropathic pain following peripheral nerve injury through both the NO-cGMP-PKG and the NO-peroxynitrite pathways.

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Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 26 January 2018

Publication date (Electronic): 3 January 2018

Volume: 9

Issue: 7

Pages: 7513-7521

Affiliations

¹ Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China

² Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China

³ Department of Anesthesiology, Guangzhou Women and Children’s Medical Center, Guangzhou, China

⁴ Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China

Author notes

Correspondence to: Peng Yao, proyaopeng@ 123456163.com

Guangyu Zhou, zhougy@ 123456sj-hospital.org

Article

Publisher ID: 23867

DOI: 10.18632/oncotarget.23867

PMC ID: 5800920

PubMed ID: 29484128

SO-VID: 0f83a01d-1746-410b-974e-ddd464f5c34a

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Early hyperbaric oxygen effects on neuropathic pain and nitric oxide synthase isoforms in CCI rats

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Most cited references 31

Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury.

Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord.

Pharmacological assessments of nitric oxide synthase isoforms and downstream diversity of NO signaling in the maintenance of thermal and mechanical hypersensitivity after peripheral nerve injury in mice.

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