Abstract:

The central component that establishes chronic pain from peripheral nerve injury is associated with increased tumor necrosis factor-alpha (TNFalpha) production in the brain. This study examined TNFalpha and its reciprocally permissive role with alpha(2)-adrenergic activation during peak and progressive decline of thermal hyperalgesia in sciatic nerve chronic constriction injury (CCI). Accumulation of TNFalpha mRNA (in situ hybridization) increases in the hippocampus and locus coeruleus during the onset of neuropathic pain and persists as hyperalgesia abates. Activation of alpha(2)-adrenergic receptors in control rats decreases TNFalpha mRNA accumulation in these brain regions. In contrast, during hyperalgesia, alpha(2)-adrenergic activation enhances TNFalpha mRNA accumulation. Whether this enhanced TNFalpha production is associated with changes in the regulation of norepinephrine (NE) release was tested. Hippocampal slices were electrically depolarized to evaluate alpha(2)-adrenergic and TNFalpha regulation of NE release. While inhibition of NE release by TNFalpha is maximal during peak hyperalgesia, it subsequently transforms to facilitate NE release. In addition, alpha(2)-adrenergic receptor activation with clonidine (0.2mg/kg, i.p.) in CCI rats experiencing hyperalgesia restores TNFalpha and alpha(2)-adrenergic inhibition of NE release. While TNFalpha directs the development of hyperalgesia, it also directs its resolution. Transformed sensitivity to alpha(2)-adrenergic agonists during hyperalgesia demonstrates a mechanism for therapy.

Open in

PUBMED | DOI | PMC | Google Scholar | Wikipedia

Relations:

Content

Citations

(6)

References

(58)

Grants

(2)

Conditions

(2)

Drugs

(4)

Chemicals

(4)

Organisms

(3)

Anatomy

(2)

Affiliates

(1)

Antinociception mediated by alpha<sub>2</sub>-adrenergic activation involves increasing TNFα expression and restoring TNFα and alpha<sub>2</sub>-adrenergic inhibition of norepinephrine release

^{Department of Pathology and Anatomical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214}

^{Department of Anesthesiology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214}

Corresponding Author: Tracey A. Ignatowski, Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 206 Farber Hall, 3435 Main St., Buffalo, NY 14214, phone: (716) 829-3102, fax: (716) 829-2086, E-mail: ude.olaffub@1iat

Copyright notice

Publisher's Disclaimer

Abstract

The central component that establishes chronic pain from peripheral nerve injury is associated with increased tumor necrosis factor-α (TNFα) production in the brain. This study examined TNFα and its reciprocally permissive role with α₂-adrenergic activation during peak and progressive decline of thermal hyperalgesia in sciatic nerve chronic constriction injury (CCI). Accumulation of TNFα mRNA (in situ hybridization) increases in the hippocampus and locus coeruleus during the onset of neuropathic pain and persists as hyperalgesia abates. Activation of α₂-adrenergic receptors in control rats decreases TNFα mRNA accumulation in these brain regions. In contrast, during hyperalgesia, α₂-adrenergic activation enhances TNFα mRNA accumulation. Whether this enhanced TNFα production is associated with changes in the regulation of norepinephrine (NE) release was tested. Hippocampal slices were electrically depolarized to evaluate α₂-adrenergic and TNFα regulation of NE release. While inhibition of NE release by TNFα is maximal during peak hyperalgesia, it subsequently transforms to facilitate NE release. In addition, α₂-adrenergic receptor activation with clonidine (0.2 mg/kg, i.p.) in CCI rats experiencing hyperalgesia restores TNFα and α₂-adrenergic inhibition of NE release. While TNFα directs the development of hyperalgesia, it also directs its resolution. Transformed sensitivity to α₂-adrenergic agonists during hyperalgesia demonstrates a mechanism for therapy.

Keywords: Neuropathic pain, Tumor necrosis factor-α, Hyperalgesia, α₂-Adrenergic receptor, Norepinephrine, In situ hybridization

Abstract

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Footnotes

Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.

Learn More