The Involvement of µ-Opioid Receptors in the Central Nervous System in the Worsening of Allergic Airway Inflammation by Psychological Stress in Mice

Abstract

Background: Psychological stress has a recognized association with asthma symptoms. However, the mechanisms linking stress to the exacerbation of asthma are not well defined. µ-Opioid receptors (MOR) have been shown to be involved in the shift of the immune system toward a Th2-predominant response caused by psychological stress. Objective: To test the hypothesis that MOR play a role in the worsening of allergic airway inflammation evoked by psychological stress. Methods: Sensitized mice were exposed to restraint stress followed by antigen challenge. The levels of corticosterone and ovalbumin (OVA)-specific IgE in the blood and the levels of inflammatory cells and cytokine contents in bronchoalveolar lavage fluid were compared between stressed and nonstressed mice. The effects of MOR gene deletion and MOR antagonists/agonists were also investigated. Results: Stress exposure was confirmed by an increase in corticosterone levels. Although OVA-specific IgE levels were not significantly different, the numbers of inflammatory cells and Th2 cytokine levels after antigen challenge in stressed mice were significantly higher than in nonstressed mice. MOR gene deletion ameliorated the stress-induced worsening of antigen-induced airway inflammation, and the administration of morphine, a MOR agonist, reproduced the stress-induced antigen-induced airway inflammation. Selective blocking of MOR in the central nervous system (CNS) significantly reduced stress-induced inflammatory exacerbation, but the blocking of peripheral MOR did not. Conclusions: MOR in the CNS are involved in psychological stress-induced aggravation of allergic airway inflammation.

The Involvement of Glucocorticoids in Psychological Stress-Induced Exacerbations of Experimental Allergic Asthma

“…Mice (6-8 weeks old) were sensitized and were made to inhale antigen as previously described [25]. Briefly, they were sensitized by i.p.…”

“…injection of ovalbumin (OVA; Grade V, Sigma, St. Louis, Mo., USA; 8 µg/mouse) adsorbed with aluminum hydroxide (Wako Pure Chemical Industries, Osaka, Japan) on days 0 and 5. On days 17 and 24, mice were challenged with aerosolized OVA for 1 h. For RS, each mouse was placed in a 50-ml conical centrifuge tube with multiple ventilation holes for 6 h per day [25]. For FSS, each mouse was forced to swim in a plastic tank containing 20 cm of deep water (32°C) for 3 min/day [24].…”

“…After each swim, the mice were immediately removed from the tank, dried with a towel and returned to their home cages. The RS and FSS are generally regarded as inducing psychological stress in the animal [24,25]. On day 17, the stressed mice in the 50-ml conical centrifuge tubes were left in plastic chambers for 6 h. For the first hour, OVA flowed through the chambers so that the mice were exposed to it.…”

“…In addition, the involvement of central nervous system activation in stress-induced asthma exacerbation has been demonstrated using functional magnetic resonance imaging [22]. In animal models of asthma, various types of psychological stress including electric foot shock stress (FS), sound stress, restraint stress (RS) and forced swimming stress (FSS) have been shown to exacerbate allergen-induced airway inflammation [23,24,25]. However, the precise mechanisms by which psychological stress aggravates Th2 immune responses have still to be clarified.…”

“…Recently, we demonstrated that RS was associated with the increased secretion of GC and leads to increased airway inflammation measured by inflammatory cell accumulation and Th2 cytokine expression, following allergen inhalation subsequent to stress in a murine model of allergic asthma [25]. In addition, a Th2 cytokine profile was predominant, and the development of Treg cells was reduced in cultures of draining lymph node cells from stressed mice when compared with nonstressed mice [26].…”