Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients
Christine B. Sieberg,
Caitlin Taras,
Aya Gomaa,
Chelsea Nickerson,
Cindy Wong,
Catherine Ward,
Georgios Baskozos,
David L.H. Bennett,
Juan D. Ramirez,
Andreas C. Themistocleous,
Andrew S.C. Rice,
Pallai R. Shillo,
Solomon Tesfaye,
Robert R. Edwards,
Nick A. Andrews,
Charles Berde,
Michael Costigan
Affiliations
Christine B. Sieberg
aDepartment of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
Caitlin Taras
dDepartment of Neurobiology, Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Aya Gomaa
dDepartment of Neurobiology, Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Chelsea Nickerson
dDepartment of Neurobiology, Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Cindy Wong
bDepartment of Psychiatry, Harvard Medical School, Boston, MA, USA
Catherine Ward
dDepartment of Neurobiology, Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Georgios Baskozos
eNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, nited Kingdom
David L.H. Bennett
eNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, nited Kingdom
Juan D. Ramirez
eNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, nited Kingdom
Andreas C. Themistocleous
eNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, nited Kingdom
Andrew S.C. Rice
gPain Research Group, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London, United Kingdom
Pallai R. Shillo
hDiabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
Solomon Tesfaye
hDiabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
Robert R. Edwards
iDepartment of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Nick A. Andrews
dDepartment of Neurobiology, Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Charles Berde
aDepartment of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
Michael Costigan
aDepartment of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
Abstract. Background:. Epidemiological studies in patients with neuropathic pain demonstrate a strong association with psychiatric conditions such as anxiety; however, the precipitating pathology between these symptoms remains unclear. To investigate this, we studied the effects of lifelong stress on levels of neuropathic pain–like behavior and conversely, the effects of chronic neuropathic injury on anxiety-like status in male and female mice. In addition, we assayed this link in painful and painless diabetic peripheral neuropathy patients. Methods:. Male and female mice were subject to ongoing life-stress or control living conditions. Baseline sensitivity and anxiety tests were measured followed by spared nerve injury (SNI) to the sciatic nerve. Subsequent sensory testing occurred until 3 weeks after SNI followed by anxiety tests between 4 and 6 weeks after SNI. Results:. Levels of tactile or cold allodynia did not differ between adult mice subject to lifelong chronic stress, relative to nonstressed controls, for at least 3 weeks after SNI. By contrast, longer-term neuropathic mice of both sexes displayed pronounced anxiety-like behavior, regardless of exposure to stress. If sex differences were present, females usually exhibited more pronounced anxiety-like behavior. These ongoing anxiety behaviors were corroborated with plasma corticosterone levels in distinct animal groups. In addition, data from patients with painful and nonpainful diabetic neuropathy showed a clear relationship between ongoing pain and anxiety, with females generally more affected than males. Discussion:. Taken together, these data demonstrate a strong link between chronic neuropathic pain and chronic anxiety, with the driver of this comorbidity being neuropathic pain as opposed to on-going stress.
