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PACAP receptors were identified in various tissues of the micturition pathway, including bladder detrusor smooth muscle and urothelium. Bladder smooth muscle expressed heterogeneously PAC<jats:sub>1<\/jats:sub>null, PAC<jats:sub>1<\/jats:sub>HOP1, and VPAC<jats:sub>2<\/jats:sub>receptors; the urothelium was more restricted in expressing preferentially the PAC<jats:sub>1<\/jats:sub>receptor subtype only. Immunocytochemical studies for PAC<jats:sub>1<\/jats:sub>receptors were consistent with these tissue distributions. Furthermore, the addition of 50\u2013100 nM PACAP27 or PACAP38 to isolated bladder strips elicited transient contractions and sustained increases in the amplitude of spontaneous phasic contractions. Treatment of the bladder strips with tetrodotoxin (1 \u03bcM) did not alter the spontaneous phasic contractions suggesting direct PACAP effects on bladder smooth muscle. PACAP also increased the amplitude of nerve-evoked contractions. By contrast, vasoactive intestinal polypeptide had no direct effects on bladder smooth muscle. In a rat cyclophosphamide (CYP)-induced cystitis paradigm, intrathecal or intravesical administration of PAC<jats:sub>1<\/jats:sub>receptor antagonist, PACAP6\u201338, reduced cystitis-induced bladder overactivity. 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