Nicotine dependence produces hyperalgesia: role of corticotropin-releasing factor-1 receptors (CRF1Rs) in the central amygdala (CeA)

Abstract

Because tobacco use has a large negative health and financial impact on society, it is critical to identify the factors that drive excessive use. These factors include the aversive withdrawal symptoms that manifest upon cessation of tobacco use, and may include increases in nociceptive processing. Corticotropin-releasing factor (CRF) signalling in the central amygdala (CeA) has been attributed an important role in: (1) central processing of pain, (2) excessive nicotine use that results in nicotine dependence, and (3) in mediating the aversive symptoms that manifest following cessation of tobacco exposure. Here, we describe three experiments in which the main hypothesis was that CRF/CRF1 receptor (CRF1R) signalling in the CeA mediates nicotine withdrawal-induced increases in nociceptive sensitivity in rats that are dependent on nicotine. In Experiment 1, nicotine-dependent rats withdrawn from chronic intermittent (14-h/day) nicotine vapor exhibited decreased hind paw withdrawal latencies in response to a painful thermal stimulus in the Hargreaves test, and this effect was attenuated by systemic administration of the CRF1R antagonist, R121919. In Experiment 2, nicotine-dependent rats withdrawn from nicotine vapor exhibited robust increases in mRNA for CRF and CRF1Rs in CeA. In Experiment 3, intra-CeA administration of R121919 reduced thermal nociception only in nicotine-dependent rats. Collectively, these results suggest that nicotine dependence increases CRF/CRF1R signalling in the CeA that mediates withdrawal-induced increases in sensitivity to a painful stimulus. Future studies will build on these findings by exploring the hypothesis that nicotine withdrawal-induced reduction in pain thresholds drive excessive nicotine use via CRF/CRF1R signalling pathways.

Keywords: CRF1 receptor; Hargreaves; Nicotine dependence; R121919; Withdrawal.

Figure 1. Nicotine-dependent rats exhibit heightened thermal sensitivity during nicotine withdrawal

Mean (+/− SEM) hind paw withdrawal latencies in response to a thermal stimulus by nicotine-dependent rats (n=7; black bars) and nicotine-naïve rats (n=8; white bars) following systemic administration of R121919 (10 mg/kg) or an equivalent volume of vehicle. *p<0.05 nicotine-dependent rats vs. controls; #p<0.05 6 hrs vs. 72 hrs withdrawal time points.

Figure 2. Nicotine dependence increases CRF and CRF1R mRNA in CeA

(A) Mean (+/− SEM) CRF mRNA expression in CeA as percent of control for nicotine-dependent (n=7; black bars) and nicotine-naïve (n=7; white bars) rats. (B) Mean (+/− SEM) CRF1R mRNA expression in CeA as percent of control nicotine-dependent (n=6; black bars) and nicotine-naïve (n=6; white bars) rats. (C) Scatter plot for individual rats (n=13 rats with values for both CRF and CRF1R) shows that CRF mRNA expression in CeA is strongly and positively correlated with CRF1R mRNA expression in CeA. *p≤0.05 nicotine-dependent rats vs. controls.

Figure 3. Antagonism of CRF1Rs in CeA Abolishes Nicotine Dependence-Induced Hyperlagesia

(A) Mean (+/− SEM) baseline thermal withdrawal latencies before and after bilateral cannulation of CeA in nicotine-dependent (n=6; black bars) and nicotine-naïve (n=6; white bars) rats. (B) Mean (+/− SEM) thermal withdrawal latencies in nicotine-dependent (n=6; black circles) and nicotine-naïve (n=6; white circles) rats. *p<0.01 nicotine-dependent rats vs. controls; #p<0.01 R121919 dose vs. vehicle condition for nicotine-dependent rats.