Sensitization of capsaicin-sensitive lung vagal afferents by anandamide in rats: role of transient receptor potential vanilloid 1 receptors

Abstract

, an arachidonic acid derivative produced during inflammatory conditions, is an endogenous agonist of both transient receptor potential vanilloid 1 (TRPV1) receptors and cannabinoid CB1 receptors. Sensitization of capsaicin-sensitive lung vagal afferent (CSLVA) fibers by chemical mediators is important in the pathogenesis of hyperreactive airway diseases. We investigated the effect of the intravenous infusion of AEA (2 mg ⅐ kg Ϫ1 ⅐ ml Ϫ1 , 0.5 ml/min for 2 min) on the sensitivity of CSLVA fibers to chemical and mechanical stimulation in anesthetized rats. In artificially ventilated rats, AEA infusion only mildly elevated the baseline activity of CSLVA fibers. However, CSLVA fiber responses to right atrial injection of capsaicin, AEA, or adenosine and to lung inflation (tracheal pressure ϭ 30 cmH2O) were all markedly potentiated during AEA infusion, which reverted 20 min after termination of the infusion. The potentiating effect on the sensitivity of CSLVA fibers to adenosine injection or lung inflation was completely blocked by pretreatment with capsazepine (a TRPV1 receptor antagonist) but was unaffected by pretreatment with AM281 (a CB1 receptor antagonist). In spontaneously breathing rats, right atrial injection of adenosine evoked an apneic response that is presumably mediated through CSLVA fibers. Similarly, the adenosine-evoked apneic response was potentiated during AEA infusion, and this potentiating effect was also completely prevented by pretreatment with capsazepine. These results suggest that AEA infusion at the dose tested produces a mild activation of TRPV1 receptors and this nonspecifically increases CSLVA fiber sensitivity to chemical and mechanical stimulation.capsaicin-sensitive lung vagal afferent fibers; afferent sensitization CAPSAICIN-SENSITIVE LUNG VAGAL afferents (CSLVAs), mainly C fibers and some A-␦ fibers, are nociceptive-like free nerve endings that play an important role in the regulation of respiratory functions under both normal and pathophysiological conditions (6,30,33,45). These lung afferent fibers can be stimulated by a variety of chemical mediators (30,34,40,45) or inhaled irritants (6,26,27,30), leading to elicitation of various airway reflexes including cough and bronchoconstriction (6, 30). Thus the sensitization of CSLVA fibers by inflammatory mediators has been implicated in the pathogenesis of hyperreactive airway diseases such as chronic cough and asthma (31,50).Studies of the afferent responses of CSLVA fibers to certain agonists have revealed that various types of pharmacological receptors may be located on the membrane of their nerve terminals (30, 45). Activation of several types of these pharmacological receptors by chemical mediators may result in sensitization of the CSLVA fibers. For examples, previous investigations have shown that bradykinin (14), histamine (29), prostaglandin E 2 (19, 25), adenosine (18), and epinephrine (17), possibly via activation of their specific receptors, increase the excitability of CSLVA fibers or vagal airway capsaicinsensitive affe...

Sensitization by Pulmonary Reactive Oxygen Species of Rat Vagal Lung C-Fibers: The Roles of the TRPV1, TRPA1, and P2X Receptors

“…Perhaps, a mild and more persistent activation of these receptors by H 2 O 2 is able to sensitize VLCFs. This notion is in agreement with previous findings indicating that a mild and prolonged activation of TRPV1 [28] and adenosine A1 receptors [38] by their agonists is able to lead to an augmentation of VLCF responses to chemical stimulants. This notion also gains supports from previous observations where it was demonstrated that the activation of bradykinin [39], prostanoid [40], histamine [41], and TRPA1 receptors [42] by their agonists is able to nonspecifically increase the excitability of VLCFs.…”

“…Additionally, studies investigating the responses of VLCFs to oxidants have suggested that ROS derived from the oxidants may activate these three types of receptors [18], [24]–[27]. Importantly, it has been proposed that these three types of pharmacological receptors have roles in the development of the airway hypersensitivity that is mediated by airway C-fibers [1], [2], [14], [15], [28], [29]. Taken together, these lines of evidence lend support to the possibility that the TRPV1, TRPA1, and P2X receptors are likely to play contributory roles in ROS-induced VLCF-mediated airway hypersensitivity.…”

Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

“…Fiber activity arising from CSLV afferents was recorded in the anesthetized, artificially ventilated rats by using the techniques described in our previous studies (14,(25)(26)(27). In brief, the trachea was cannulated and tracheal pressure was measured via a sideport of the cannula.…”

“…CSLV afferents can detect several inhaled irritants (22, 25) and inflammatory mediators (16,25,26,39) that might in turn trigger various respiratory reflexes such as cough, mucus secretion, and bronchoconstriction (7,22). The afferents are sensitized by several mediators released because of lung inflammation (2,7,15,27), which might then exaggerate these respiratory reflexes. Therefore, the sensitization of CSLV afferents is probably involved in the pathogenesis of airway hypersensitivity in diseases such as chronic cough and asthma (7, 26, 47).…”

Direct Anandamide Activation of TRPV1 Produces Divergent Calcium and Current Responses

“…Membrane lipids may serve as a predominant endogenous ligand at TRPV1 considering the relative stability of temperature and pH within the central nervous system. Peripherally, AEA is reported to sensitize and activate vagal afferents via a TRPV1 dependent mechanism (Kagaya et al, 2002; Lee et al, 2003; Lin et al, 2009). In the central nervous system, postsynaptic generation and release of AEA can act presynaptically via cannabinoid receptors to inhibit glutamate release (Kreitzer and Regehr, 2002) and may also activate TRPV1 in synapses where it is expressed.…”