2. Academic Validation
  3. Dual activation of 5-HT1A and μ-opioid receptors mediates dezocine's antidepressant effects in mice with comorbid pain and depression

Dual activation of 5-HT1A and μ-opioid receptors mediates dezocine's antidepressant effects in mice with comorbid pain and depression

  • Pharmacol Biochem Behav. 2026 Feb:259:174136. doi: 10.1016/j.pbb.2025.174136.
Qian-Qian Wei 1,  Kun-Hong Zhong 2,  Xiao-Ke Zhang 2,  Liangxue Zhou 3,  Qing Zhu 4,  Junxu Li 5
Affiliations

Affiliations

  • 1 Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Neurosurgery, NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, Sichuan, China; Department of Neurosurgery, Fifth People's Hospital of Ningxia Hui Autonomous Region, Shizuishan, 753000, Ningxia, China. Electronic address: [email protected].
  • 4 School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial Key Laboratory of Inflammation and Molecular Drug Target, Nantong 226001, Jiangsu, China. Electronic address: [email protected].
  • 5 School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China. Electronic address: [email protected].
PMID: 41365431 DOI: 10.1016/j.pbb.2025.174136
Abstract

Background: Pain-depression morbidity affects millions, but there are no effective treatments available. Dezocine is a clinically used opioid analgesic with complicated pharmacological mechanisms. Given this unique pharmacological profile and the crucial involvement of noradrenergic/serotonergic systems in the pathophysiology of depression, dezocine might be able to relieve pain-depression comorbidity. This possibility has not been tested and is the focus of this study. However, this potential has not yet been empirically validated, and investigating it constitutes the primary aim of this study.

Methods: Animal models of depression (Lipopolysaccharides [LPS] and chronic unpredictable mild stress models [CUMS]) were established, and two neuropathic pain models (chronic constriction injury [CCI] and spared nerve injury [SNI]) were used to establish chronic pain-induced depressive-like behaviors and the antidepressive-like effects of dezocine were then examined. Tail suspension test (TST) and force swimming test (FST) were used as behavioral readouts of antidepressant effects. For receptor mechanisms studies, 5-HT1A receptor antagonist WAY-100635, nonselective Opioid Receptor Antagonist naltrexone [NTX]), and three selective Opioid Receptor antagonists (μ: CTAP; δ: naltrindole [NAL]; k: nor-binaltorphimine [nor-BNI]) were used as pretreatment to antagonize the effects of dezocine.

Results: Dezocine (5 and 10 mg/kg, i.p.) significantly reduced immobility time, suggesting its robust antidepressive-like effects in stand-alone depression models and in neuropathic pain-induced depression models. WAY-100635, NTX, and CTAP but not NAL or nBNI blocked the antidepressive-like effects of dezocine, suggesting the involvement of 5-HT1A and μ-opioid receptors in mediating the antidepressive-like effects of dezocine.

Conclusion: This study demonstrates that dezocine alleviates pain-depression comorbidity by activating both 5-HT1A and μ-opioid receptor.

Keywords

Antidepressant; Dezocine; Neuropathic pain; Opioids; Serotonin.

Figures
Products