WAY-100635

This study aimed to investigate the role of 5-hydroxytryptamine 1A (5-HT_1A) receptors in the anterior cingulate cortex (ACC) in regulating the affective pain in rats. In the ACC, normal saline (NS), the 5-HT_1A receptor agonist 8-OH-DPAT or the 5-HT_1A receptor antagonist WAY-100635 was pre-injected respectively. A persistent inflammatory pain model was established by subcutaneously injecting 0.08 mL of complete Freund's adjuvant (CFA) into the left hind paw of rats, which was then paired with a specific environment to induce a conditioned place avoidance (CPA) response. Then the electroacupuncture (EA, 10 Hz, 3 mA) was applied to stimulate the Huantiao acupoint (GB30). The CPA responses of rats in the pain-paired environment and the firing activities of ACC neurons were simultaneously observed. Subsequently, open-field behavior, paw withdrawal latency (PWL), and 50% paw withdrawal threshold (PWT) tests were conducted. The results showed that: (1) Rats injected with CFA showed significant reductions in PWL and 50% PWT, and spent less time in the "pain-paired environment" and the center of the open field, compared to the control group (P < 0.05). (2) Immunofluorescence double-labeling results showed a high co-expression of Fos protein and 5-HT_1A receptors in the ACC of the EA-treated normal rats. (3) Pre-treatment with the 5-HT_1A receptor agonist 8-OH-DPAT (8 μg) in the ACC alleviated CFA-induced affective pain (P < 0.05) and reversed the increase in firing frequency of pyramidal neurons in the ACC induced by CFA (P < 0.05). (4) Pre-treatment with the 5-HT_1A receptor antagonist WAY-100635 (8 μg) in the ACC, combined with EA stimulation, reversed the CPA-like behavioral responses induced by CFA in rats and increased the firing frequency of pyramidal neurons in the ACC (P < 0.05). These results suggest that the 5-HT_1A receptors in ACC mediate the alleviating effect of EA on the affective pain of CFA-induced rats.

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.

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-HT_1A 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.

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-HT_1A and μ-opioid receptors in mediating the antidepressive-like effects of dezocine.

This study demonstrates that dezocine alleviates pain-depression comorbidity by activating both 5-HT_1A and μ-opioid receptor.