There are several protective reflexes initiated by trigeminal sensory afferent nerves, such as sneezing, cough, mucus secretion, and bronchoconstriction that are essential for expelling or neutralizing irritants and allergens from the respiratory system. Transient Receptor Potential (TRP) ion channels, such as TRPV1 (vanilloid) and the TRPA1 (ankyrin), on non-myelinated C fibers of trigeminal sensory nerves that innervate the nasal mucosa, are sensors of inhaled irritants (Geppetti et al. 2010). The vanilloid subtype, TRPV1, is an integrative, multigated ion channel widely expressed in human nasal epithelium and neuronal tissue and is known to be activated typically by capsaicin, protons and heat (Szolcsányi and Sándor 2012; Cao et al. 2013; Brauchi et al. 2006; Myers et al. 2008). This channel is believed to be important in a spectrum of important physiological functions that are inhibited in cell or animal models that have TRPV1 gene deletion (White et al. 2011; Szolcsányi 2008). On the other hand, development of nasal hyper-responsiveness to environmental factors that may initiate symptoms of rhinitis may be caused by TRPV1 hyperactivity (Lambert et al. 2013). Neuropeptides such as SP and CGRP secreted as a result of stimulation of these afferent nerves cause vasodilatation, increased vascular permeability, and glandular secretion that can explain many of the symptoms associated with chronic rhinitis (Pfaar et al. 2009). It is also known that TRP channel activation is also highly regulated by neuropeptides such as SP and CGRP (Chung et al. 2008).

TRPV1 channels interact and regulate other colocalized TRP channels (e.g., TRPA1) and ion channels (e.g., Na⁺ channels) (Raisinghani et al. 2011). Intracellular cascades triggered by other G-protein coupled receptors such as bradykinin receptors (B2R) have been demonstrated to further sensitize these channels. (Szolcsányi and Pintér 2013; Mizumura et al. 2005).

Changes in the regulatory mechanisms that control TRPV1 channel function can result in pathologic alteration of its activity. N-glycosylation of the TRPV1 channel affects pharmacokinetics (EC50) and dose–response curves of TRPV1 agonists (Wirkner et al. 2005). Thus, any pathological alteration in TRPV1 glycosylation may cause TRPV1 channel hyper-responsiveness (Veldhuis et al. 2012). TRPV1 N-glycosylation facilitates TRPV1 pore dilation and therefore significantly reduces agonist-induced desensitization of these channels. Pore dilation confers resistance to channel desensitization or conformational changes to desensitized state. Interestingly, glycosylation end products have been found to be elevated in patients with AR (Di Lorenzo et al. 2013), but such changes have not been investigated for NAR.

Capsaicin-gated TRPV1 conductance is regulated by calcium in a concentration and voltage dependent manner by causing hyperpolarizing shifts in the voltage dependence of these channels (Aneiros et al. 2011; Blanchard and Kellenberger 2011). Capsaicin-induced TRPV1 activation hydrolyzes the membrane phosphatidylinositol 4, 5-bisphosphate PIP2 and its subsequent depletion has been shown to occur in parallel with TRPV1 ion channel activation (Akopian et al. 2007). Recovery of the channel from the desensitized state is determined by replenishment of PIP2 in the cell membrane (Liu et al. 2005). It has been demonstrated that TRPV1 desensitization to repeated applications of capsaicin (tachyphylaxis) is prevented by ATP or PIP2, while calmodulin was necessary for sustaining tachyphylaxis (Lishko et al. 2007). Interestingly, another study has shown that PIP2 along with PIP4 inhibits TRPV1 leading investigators to conclude that the phosphoinositide turnover contributes to thermal hyperalgesia by blocking inhibition of the channel (Cao et al. 2013). In addition, PKC and PKA mediated phosphorylation sensitizes TRPV1 channels by promoting downstream changes in channel activation that enhances the channel opening time rather than by a direct action of phosphorylation on the capsaicin binding site (Brauchi et al. 2006; Samways and Egan 2011; Studer and McNaughton 2010; Garcia-Sanz et al. 2007). Novel proteins associated with GABA receptors have been identified to be associated with TRPV1 signaling complex. These proteins increase trafficking and surface expression of TRPV1, besides modulating channel gating and sensitivity (Lainez et al. 2010).

Surgical denervation of sensory or autonomic nerves as well as treatment with intranasal capsaicin has been demonstrated to reduce glandular secretions and mucosal permeability and therefore relieve symptoms of NAR (Norlander et al. 1996; Baraniuk 1992; Baraniuk and Kaliner 1991). Capsaicin has been shown to reduce mucosal permeability without affecting tight junction of the nasal mucosal epithelium (Jeon et al. 1995). It causes sensory neurons important for relaying pain signals from the nasal cavity to become hyposensitive. As these cells become less hyper-reactive, neurogenic pain signals are significantly reduced. Capsaicin also depletes SP stores in nerve cells. Because SP may dilate nasal blood vessels and increase secretions from mucosal membranes, the depletion of SP stores in nerve cells by capsaicin can also relieve chronic painful sinus conditions. This observation is supported by previous studies that demonstrated that capsaicin-induced TRPV1 desensitization decreases the number of CGRP and SP immune reactive cells, without causing axonal degeneration of urinary bladder nerve fibers in animal models (Avelino and Cruz 2000). Analogous mechanisms may explain observed neuropeptide depletion induced by capsaicin in nasal mucosal glands (Blom et al. 1997). Repeated intranasal capsaicin application has been shown to reduce nasal vascular responses in patients with rhinitis which correlates with reduction of the CGRP-like immunoreactivity in nasal biopsies (Lacroix et al. 1991). Several other potential mechanisms of action for capsaicin continue to be investigated which may further help elucidate the mechanism(s) for underlying complex disorders such as NAR and headache.

Double-blind, placebo-controlled studies have demonstrated that capsaicin provides both significant short- and long-term reduction of symptoms in NAR patients. More recently published controlled trials have demonstrated that capsaicin can be safely administered without having to anesthetize the nose and causes no significant adverse effects (Blom et al. 1997, 1998; Bernstein et al. 2011a, b). Capsaicin and its derivatives have also been demonstrated in controlled studies to reduce the frequency and severity of cluster, migraine, and tension headaches (Fusco et al. 2003).

Table 6.1 summarizes some of the important clinical trials investigating the effects of capsaicin in AR, NAR, or MR as well as on headache and sinusitis. Clinical trials investigating the therapeutic benefit of capsaicin on patients with AR did not find significant effect in reducing nasal hyper-reactivity or in improving rhinorrhea (Gerth Van Wijk et al. 2000). However, some of these trials were able to demonstrate that increased plasma protein extravasation or leucocyte infiltration is neurally mediated through sensory afferents nerves innervating the nasal mucosa (Sanico et al. 1997, 1998a, b). In contrast, a number of clinical trials have described significant therapeutic efficacy and safety of chronic usage of local capsaicin formulations, when used to treat NAR and MR compared to placebo therapies (Bernstein et al. 2011a, b; Ciabatti and D’Ascanio 2009; Zheng et al. 2000; Filiaci et al. 1994, 1996; Rinder 1996; Marabini et al. 1991). Because all of these trials implemented different study designs and dosing regimens, the ability to compare primary endpoints is significantly limited (Table 6.1) (Bernstein et al. 2011a, b; Filiaci et al. 1996; Marabini et al. 1991; Van Rijswijk et al. 2003; Latimer and Poston 1976).