Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain

Ya Chun Chu; Yun Guan; John Skinner; Srinivasa N. Raja; Roger A. Johns; Yuan Xiang Tao

doi:10.1016/j.pain.2005.09.024

Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain

Ya Chun Chu, Yun Guan, John Skinner, Srinivasa N. Raja, Roger A. Johns, Yuan Xiang Tao

School of Medicine

Research output: Contribution to journal › Article › peer-review

89 Scopus citations

Abstract

Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-N^G-nitro- arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2 h) and maintenance (24 h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24 h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24 h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.

Original language	English (US)
Pages (from-to)	113-123
Number of pages	11
Journal	Pain
Volume	119
Issue number	1-3
DOIs	https://doi.org/10.1016/j.pain.2005.09.024
State	Published - Dec 15 2005

Keywords

Allodynia
Central sensitization
Chronic pain
Hyperalgesia
Nitric oxide
Spinal cord

ASJC Scopus subject areas

Neurology
Clinical Neurology
Anesthesiology and Pain Medicine

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10.1016/j.pain.2005.09.024

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title = "Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain",

abstract = "Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-NG-nitro- arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2 h) and maintenance (24 h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24 h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24 h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.",

keywords = "Allodynia, Central sensitization, Chronic pain, Hyperalgesia, Nitric oxide, Spinal cord",

author = "Chu, {Ya Chun} and Yun Guan and John Skinner and Raja, {Srinivasa N.} and Johns, {Roger A.} and Tao, {Yuan Xiang}",

note = "Funding Information: This work was supported by the Johns Hopkins University Blaustein Pain Research Fund and NIH grants RO1 NS44219 and GM 49111. The authors would like to thank Tzipora Sofare, MA, for her editorial assistance. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

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AU - Guan, Yun

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AU - Raja, Srinivasa N.

AU - Johns, Roger A.

AU - Tao, Yuan Xiang

N1 - Funding Information: This work was supported by the Johns Hopkins University Blaustein Pain Research Fund and NIH grants RO1 NS44219 and GM 49111. The authors would like to thank Tzipora Sofare, MA, for her editorial assistance. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2005/12/15

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N2 - Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-NG-nitro- arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2 h) and maintenance (24 h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24 h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24 h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.

AB - Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-NG-nitro- arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2 h) and maintenance (24 h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24 h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24 h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.

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Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain

Abstract

Keywords

ASJC Scopus subject areas

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