7: Impact of chronic pain on negative affective state during nicotine withdrawal in male rats

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Developing methodology/technology, Assessment and Measurement of Pain/Nociception, Behavioral studies

Background and Aims: Chronic pain is a major public health problem worldwide and it is often associated with negative affect (1-3). Nicotine use is also a widespread global health problem, and nicotine withdrawal induces negative affect (4). However, it remains unclear how chronic pain influences negative affect during nicotine withdrawal. In this study, we aimed to examine affective behaviors in male rats during nicotine withdrawal in the presence or absence of chronic pain.

Methods: Chronic pain was induced in adult male Sprague Dawley rats using the chronic constriction injury (CCI) model, and mechanical sensitivity was assessed using the von Frey test (5). Two weeks after CCI surgery, rats received twice daily subcutaneous injections of nicotine at 0.3 or 0.7 mg/kg or saline for 14 days. Affective behaviors were assessed during spontaneous nicotine withdrawal, 24 hours after the final injection, using somatic sign scoring, the light-dark box test, the marble burying test, and a social interaction test (6).

Results: CCI-induced chronic pain remained present throughout the study. Nicotine withdrawal produced somatic signs in a dose-dependent manner, and CCI significantly amplified these physical withdrawal symptoms. Nicotine withdrawal also increased anxiety-like behaviors, which were significantly exacerbated in the presence of CCI. In addition, CCI significantly reduced social interaction. Nicotine exposure at both doses restored social preference in CCI rats, whereas nicotine had no effect on social behavior in control rats.

Conclusions: Together, these findings demonstrate that chronic pain exacerbates both the physical and negative affective symptoms of nicotine withdrawal, while nicotine exposure normalizes pain-associated social deficits, highlighting a complex interaction between chronic pain and nicotine withdrawal.

References: 1. Zelaya CE, Dahlhamer JM, Lucas JW, Connor EM. Chronic Pain and High-impact Chronic Pain Among U.S. Adults, 2019. NCHS Data Brief. 2020;(390):1-8.
2. Orhurhu VJ, Pittelkow TP, Hooten WM. Prevalence of smoking in adults with chronic pain. Tob Induc Dis. 2015;13(1):15-20.
3. Larowe LR, Ditre JW. Pain, nicotine, and tobacco smoking: Current state of the science. Pain. 2020;161(8):1688-1693.
4. Hall FS, Der-Avakian A, Gould TJ, Markou A, Shoaib M, Young JW. Negative affective states and cognitive impairments in nicotine dependence. Neurosci Biobehav Rev. 2015;58:168-85.
5. Bagdas D, AlSharari SD, Freitas K, Tracy M, Damaj MI. The role of alpha5 nicotinic acetylcholine receptors in mouse models of chronic inflammatory and neuropathic pain. Biochem Pharmacol. 2015;97(4):590-600.
6. Bagdas D, Alkhlaif Y, Jackson A, Carroll FI, Ditre JW, Damaj MI. New insights on the effects of varenicline on nicotine reward, withdrawal and hyperalgesia in mice. Neuropharmacology. 2018;138:72-79.

Presenting Author: Deniz Bagdas
Submitting Author: Deniz Bagdas

Senior Author: Deniz Bagdas

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Deniz Bagdas - Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA.
• Brianna Graham: BSc - Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA.
• Tyler Nelson: BSc - Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA.
• Sheela Tavakoli: BSc - Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA.
• Nii A. Addy: PhD - Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA.