Blunted opioid regulation of the HPA stress response during nicotine withdrawal: therapeutic implications

Abstract

Endogenous opioids regulate pain, drug reward, and stress responses. We have previously shown reduced hypothalamic-pituitary-adrenal (HPA) responses to psychological stress and to opioid blockade among dependent smokers. In this study, we examined the extent to which biologically confirmed nicotine withdrawal alters endogenous opioid regulation of HPA axis functioning during rest and in response to acute stress. Smokers were randomly assigned to one of two conditions; 24 h withdrawal from all nicotine-containing products (n = 62) or smoking ad libitum (n = 44). A nonsmoking comparison group (n = 43) was also included. Participants (85 males and 64 females) completed two acute stress sessions during which a placebo or 50 mg of naltrexone (opioid antagonist) were administered using a double-blind design. Blood and saliva samples (assayed for cortisol and adrenocorticotropic hormone, i.e. ACTH) and mood measures were obtained during a resting absorption period, after acute stress (public speaking, mental arithmetic, and cold pressor tasks), and during an extended recovery period. Results indicated that opioid blockade (naltrexone) was associated with increased ACTH and cortisol responses to stress, and tobacco withdrawal was associated with blunted hormonal responses. A pattern of sex differences also emerged, with women exhibiting reduced ACTH responses to stress and higher ACTH and plasma cortisol responses to opioid blockade. These results indicated that compared to ad libitum smoking, nicotine withdrawal is associated with blunted opioid modulation of the HPA axis. Sex may modulate these effects. Blunted endogenous opioid regulation may underlie an incentive process that reinforces smoking behavior and may warrant therapeutic attention.

Keywords: Endogenous opioid function; HPA; addiction; nicotine withdrawal; stress.

Figure 1.

Laboratory protocol Figure 1. Laboratory protocol. Participants sat quietly and watched Planet Earth (nature documentary) for an initial baseline period (20 min), during which blood pressure (BP) and heart rate (HR) were obtained every five minutes. Then, participants completed mood and smoking withdrawal questionnaires and the first blood and saliva samples before ingesting a capsule containing either 50 mg of naltrexone or placebo at the start of a 40-minute ‘absorption’ period. During absorption, BP and HR were obtained at 5-minute intervals; and self-report measures as well as plasma and saliva samples were collected after 20- and 40-minutes during this time. After absorption, smokers in the ad libitum condition were asked to smoke one cigarette of their preferred brand. Then, all participants completed the stress tasks, during which BP and HR were collected every 2 to 3 minutes. Self-report measures and blood and saliva samples were collected after the stress tasks and then after 30-, 60-, and 80-minutes of post-stress rest during which they continued to watch Planet Earth. BP and HR were collected every 5 minutes during the last 20 minutes of the post-stress rest period.

Figure 2.

Sex differences in drug effects on hormonal measures Figure 2. Estimated means and standard error of the mean by sex and smoking group for ACTH, plasma cortisol, and salivary cortisol collected during rest before ingestion of the drug capsule, during rest absorption period, following acute stress, and during a recovery rest period.

Figure 3.

Hormonal measures Figure 3. Estimated means and standard error of the mean for ACTH (3A), plasma cortisol (3B), and salivary cortisol (3C). Figure 3A depicts the Time x Drug interaction on ACTH. Figures 3B and 3C depict smoking group differences in the drug effect on cortisol, where AUC_Δ indexes the drug effect (AUC_naltrexone - AUC_placebo) on cortisol AUC from immediately post-stress (period 4) to after the final rest (period 7).