PACAP/PAC1 Expression and Function in Micturition Pathways

Abstract

Neural injury, inflammation, or diseases commonly and adversely affect micturition reflex function that is organized by neural circuits in the CNS and PNS. One neuropeptide receptor system, pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1), and its cognate receptor, PAC1 (Adcyap1r1), have tissue-specific distributions in the lower urinary tract. PACAP and associated receptors are expressed in the LUT and exhibit changes in expression, distribution, and function in preclinical animal models of bladder pain syndrome (BPS)/interstitial cystitis (IC), a chronic, visceral pain syndrome characterized by pain, and LUT dysfunction. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency and somatic (e.g., hindpaw, pelvic) sensitivity in preclinical animal models and a transgenic mouse model that mirrors some clinical symptoms of BPS/IC. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction following urinary bladder inflammation.

Keywords: Cyclophosphamide; Cystometry; NGF; Neuropeptides; Somatic sensation.

Figure 1:. Potential etiologic cascade and pathogenesis underlying painful bladder syndrome (BPS)/interstitial cystitis (IC).

It is likely that BPS/IC has a multifactorial etiology that may act predominantly through one or more pathways resulting in the typical symptom-complex. There is a lack of consensus regarding the etiology or pathogenesis of BPS/IC but a number of proposals include a “leaky epithelium,” release of neuroactive compounds at the level of the urinary bladder with mast cell activation, “awakening” of C-fiber bladder afferents, and upregulation of inflammatory mediators including cytokines and chemotactic cytokines (chemokines). Inflammatory mediators can affect CNS and PNS neural circuitry including central “wind-up” and nociceptor sensitization resulting in chronic bladder pain and voiding dysfunction. BPS/IC is associated with diseases affecting other viscera and pelvic floors. See text for additional details. Figure adapted from (Sant et al., 2007; Gonzalez et al., 2014).

Figure 2:. Blockade of the PACAP/receptor system in micturition reflexes is a potential strategy to improve bladder function and reduce pelvic pain following urinary bladder inflammation.

The CYP-induced bladder inflammation model in rodents and the transgenic mouse model of chronic urothelial overexpression of NGF (NGF-OE) are essential to determine underlying mechanisms contributing to urinary bladder dysfunction and pelvic pain in the clinical syndrome BPS/IC. Both models are associated with changes in NGF expression in the urinary bladder that can result in changes in the urinary bladder and be retrogradely transported to lumbosacral dorsal root ganglia (DRG). PACAP and PAC1 receptor exhibit neuroplastic changes in expression and function with CYP-induced bladder inflammation and increased NGF expression in the urinary bladder. Intravesical instillation of the PAC1 receptor antagonist, PACAP (6–38), reduces voiding frequency and somatic sensitivity. Blockade of PAC1 in micturition reflexes may represent a novel therapeutic intervention to improve urinary bladder function and reduce referred, somatic pain. DH, dorsal horn; EUS, external urethral sphincter. Figure adapted from (Girard et al., 2017).