Differential effects of activation of peripheral and spinal tachykinin neurokinin3 receptors on the micturition reflex in rats

Purpose: We clarified the roles of tachykinin neurokinin (NK)(3) receptors in the bladder or spinal cord for control of the micturition reflex in rats. Materials and Methods: In female rats under urethane anesthesia repetitive bladder contractions were elicited by saline infusion into the bladder through intravesical. bladder catheters. The effects of peripheral receptor activation were first examined by topical application of the tachykinin NK3 receptor agonist [MePhe(7)]-NKB (Calbiochem, Darmstadt, Germany) in normal rats and rats pretreated with capsaicin (Sigma Chemical Co., St. Louis, Missouri) 4 days before the experiments. Subsequently the effects of spinal NK3 receptor activation were examined by intrathecal administration of [MePhe(7)]-NKB via implanted intrathecal catheters. The effects of the tachykinin NK3 receptor antagonist SB235375 and the opioid receptor antagonist naloxone on changes in bladder activity induced by [MePhe(7)]-NKB were also investigated. Results: Topical application of [MePhe(7)]-NKB onto the bladder surface decreased intercontraction intervals and bladder capacity, and increased baseline bladder pressure in dose dependent fashion. [MePhe(7)]-NKB induced bladder overactivity was inhibited by simultaneous topical administration of SB235375 or by capsaicin pretreatment. In contrast, intrathecal injection of [MePhe(7)]-NKB increased intercontraction intervals in dose dependent fashion and at a high dose it induced overflow incontinence or inefficient voiding. These inhibitory effects of [MePhe(7)]-NKB in the spinal cord were antagonized by the intrathecal injection of SB235375 or naloxone. Conclusions: These results indicate that the tachykinin NK3 receptor mediated neural control of the micturition reflex has dual actions depending on the location of receptor activation. Activation of tachykinin NK3 receptors located in the bladder can induce bladder overactivity at least in part via the activation of capsaicin sensitive C-fiber afferents, while tachykinin NK3 receptor activation in the spinal cord can inhibit the micturition reflex through an opioid mechanism.