Background & Aims
Chronic pain, a multi- dimensional condition characterized by sensory, cognitive, and emotional symptoms, is often comorbid with mood disorders and associated with increased substance use 1. Chronic pain patients are particularly vulnerable to tobacco use, a leading cause of preventable death in the US 2,3. Smoking rates among chronic pain patients are double the national average 4,5, and they exhibit high nicotine addiction 6,7. Notably, 60% of tobacco users also experience chronic pain 8. A new model suggests a vicious cycle between chronic pain and tobacco use, with each amplifying the other 9,10. Despite this critical public health issue, the underlying mechanisms remain unclear. Notably, no preclinical model accurately captures this comorbidity, limiting our understanding. To address this gap, we developed a model to investigate the relationship between chronic pain and nicotine addiction.
Methods
First, we established a chronic constrictive nerve injury (CCI)-induced neuropathic pain model in male Sprague Dawley adult rats. Two weeks post-surgery, rats were exposed to e-cigarette liquids containing 0, 3, and 6 mg/ml free-base nicotine in 50:50 propylene glycol/vegetable glycerine via a combined passive and vapor self-administration (VSA) procedure in an e-cigarette vapor delivery system at 50W power and 400°F. For five days, rats passively received a 3-second vapor puff every 8 minutes (15 puffs/session). This was followed by 18 days of VSA (3-second puff, 30-second timeout, for 1 hour daily) through fixed-ratio schedules (FR1 for 6 days, FR3 for 5 days, and FR5 for 7 days). The active response was a vapor-paired nose poke. Mechanical hypersensitivity was measured weekly. A sham surgery group and naïve rats were also used in the study.
Results
Naïve rats displayed nicotine VSA at high (6 mg) but not low (3 mg) nicotine concentration. Nose pokes for vapor-paired holes significantly exceeded those for non-paired holes during 6mg/ml VSA. However, this pattern shifted considerably in CCI chronic pain rats. They exhibited a significant nicotine intake for the 3 mg nicotine concentration, with nose pokes for vapor-paired holes markedly exceeding those for non-paired holes. Interestingly, this nicotine-taking behavior diminished at the higher concentration (6 mg), where they did not discriminate between the vapor-paired and non-paired holes. Unlike both naïve and CCI groups, sham rats didn’t display a strong VSA for any nicotine concentration. While they showed some tendency towards VSA at the 3mg/ml concentration, their active nose pokes for vapor-paired holes were significantly lower compared to CCI rats at the same concentration.
Conclusions
While naïve rats readily established nicotine-taking behavior at the higher concentration, CCI rats established nicotine-taking behavior at the lower nicotine concentration. Although exposed to the same VSA protocol as CCI rats, sham rats developed only a moderately weaker association with nicotine taking. These findings suggest that chronic pain alters nicotine-taking behavior in rats. CCI rats preferentially sought a lower nicotine concentration than naïve rats, suggesting a potential dampening effect of chronic pain on high-dose nicotine-related motivation. It’s important to note that although sham rats exhibited some VSA at 3mg/ml, this behavior remained significantly lower than the robust nicotine taking observed in CCI rats. This distinction is key to understanding the specific role of chronic pain in modulating nicotine dependence. Further investigation is needed to elucidate the underlying mechanisms of this differential VSA behavior in the context of chronic pain.
References
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