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The purpose of this study was to determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, neurokinin 2 receptor (NK receptor) agonist, Lys, MeLeu, Nle-NKA (LMN-NKA). Cystometry and colorectal pressure measurements were performed in urethane-anesthetized, intact, and acutely spinalized female rats. Bladder pressure and voiding were monitored in response to intravenous LMN-NKA given with the bladder filled to 70% capacity. LMN-NKA (0.1-300 μg/kg) produced dose-dependent, rapid (<60 s), short-duration (<15 min) increases in bladder pressure. In intact rats, doses above 0.3-1 μg/kg induced urine release (voiding efficiency of ~70% at ≥1 μg/kg). In spinalized rats, urine release required higher doses (≥10 μg/kg) and was less efficient (30-50%). LMN-NKA (0.1-100 μg/kg) also produced dose-dependent increases in colorectal pressure. No tachyphylaxis was observed, and the responses were blocked by an NK receptor antagonist (GR159897, 1 mg/kg i.v.). No obvious cardiorespiratory effects were noted. These results suggest that rapid-onset, short-duration, drug-induced voiding is possible in acute spinal and intact rats with intravenous administration of an NK receptor agonist. Future challenges remain in regard to finding alternative routes of administration that produce clinically significant voiding, multiple times per day, in animal models of chronic SCI. [ABSTRACT FROM AUTHOR]

The effects of the tachykinin NK2 receptor agonist LMN-NKA ([Lys 5 ,MeLeu 9 ,Nle 10 ]-NKA (4-10) ) on colorectal and arterial blood pressure were examined in anesthetized macaques. Intravenous (IV) administration of 1-100 μg/kg caused dose-related increases in colorectal pressure up to 120 mmHg above baseline, and area under the curve (AUC) up to 24,987 mmHg*s. This was accompanied at all doses by transient hypotension, with up to 26% reduction in mean arterial pressure (MAP) from baseline. Hypotension, but not the increase in colorectal pressure, was inhibited by a 10-min pretreatment with the NK1 receptor antagonist CP-99,994. In a pilot experiment using subcutaneous (SC) injection, a similar dose range of LMN-NKA (3-100 μg/kg) again appeared to increase colorectal pressure with a similar AUC (up to 18,546 mmHg*s) to that seen after IV injection, but lower peak amplitude (up to 49 mmHg). Unlike the effects of IV injection, hypotension was only present after the highest SC dose (100 μg/kg) in one of two animals. Pharmacokinetic analysis revealed markedly lower plasma exposures after SC compared with IV administration. Cmax was 39.6 versus 1070 ng/mL, and AUC inf was 627 versus 2090 ng/mL*min, respectively. These findings are consistent with previous observations in anesthetized dogs and indicate that the prokinetic effects of LMN-NKA may be achieved without hypotension using a route of administration that avoids unnecessarily high plasma exposures.

Tachykinin neurokinin 2 (NK2) receptor agonists may have potential to alleviate clinical conditions associated with bladder and gastrointestinal underactivity by stimulating contraction of visceral smooth muscle. The ability of [Lys 5 ,MeLeu 9 ,Nle 10 ]-neurokinin A (4-10) (LMN-NKA) to elicit micturition and defecation was examined after repeated administration in groups of 2-10 conscious dogs. Administration of 10-100 μ g/kg, i.v., four times daily for six consecutive days, reliably elicited micturition after ≥90% of doses and defecation after ≥50% of doses. Voiding occurred <4 minutes after dosing and was short lasting (<10 minutes). LMN-NKA was well tolerated, with emesis after ∼25% of doses at 100 μ g/kg, i.v. Hypotension was induced by 100 μ g/kg, i.v., of LMN-NKA but not by lower doses. Administration of 30-300 μ g/kg, s.c., twice daily for seven consecutive days, reliably elicited both urination and defecation after 88%-100% of doses, and was accompanied by a high rate of emesis (50%-100%). The onset of voiding was rapid (<7 minutes) but was more prolonged than after intravenous administration (30-60 minutes). Emesis induced by 30 or 300 μ g/kg, s.c., of LMN-NKA was significantly reduced (from 58% to 8% and from 96% to 54%, respectively) by a 30-minute pretreatment with the neurokinin 1 (NK1) receptor antagonist, (2 S ,3 S )- N -(2-methoxybenzyl)-2-phenylpiperidin-3-amine (CP-99,994; 1 mg/kg, s.c.). The ability of selective NK2 receptor agonists to elicit on-demand voiding could potentially address a major unmet need in people lacking voluntary control of micturition and/or defecation. LMN-NKA unexpectedly activated NK1 receptors at doses that stimulated voiding, causing emesis and hypotension that may limit the clinical utility of nonselective NK2 receptor agonists., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Tachykinin NK2 receptor (NK2R) agonists have potential to alleviate clinical conditions associated with bladder and gastrointestinal under activity. The effects of agonists with differing selectivity for NK2R over NK1Rs on colorectal, bladder, and cardiovascular function were examined in anesthetized dogs. Intravenous (IV) administration of NKA, LMN-NKA ([Lys 5 ,MeLeu 9 ,Nle 10 ]-NKA (4-10) ), and [β-Ala 8 ]-NKA (4-10) caused a dose-related increase in colorectal pressure (up to 98 mmHg) that was blocked by pretreatment with the NK2R antagonist GR 159897 (1 mg/kg), and hypotension (decrease in mean arterial pressure of ~40 mmHg) that was blocked by the NK1R antagonist CP-99,994 (1 mg/kg). Despite the greater in vitro selectivity of LMN-NKA and [β-Ala 8 ]-NKA (4-10) for NK2R over NK1Rs compared with NKA, all 3 agonists increased colorectal pressure and caused hypotension within a similar dose range when administered as a bolus (0.1-300 μg/kg IV), or even as a slow IV infusion over 5 min (NKA; 0.02-0.6 μg/kg/min). In contrast, subcutaneous (SC) administration of LMN-NKA (3-10 μg/kg) increased colorectal pressure (up to 50 mmHg) and elicited micturition (≧ 85% voiding efficiency) without causing hypotension. NK2R agonists can produce rapid-onset, short-duration, colorectal contractions, and efficient voiding of urine without hypotension after SC administration, indicating that routes of administration that avoid the high plasma concentrations associated with IV dosing improve the separation between desired and unwanted pharmacodynamic effects. The potent hypotensive effect of NKA in dogs was unexpected based on published studies in humans in which IV infusion of NKA did not affect blood pressure at doses that increased gastrointestinal motility.

The suitability of various neurokinin-2 (NK2) receptor agonists and routes of administration to elicit on-demand voiding of the bladder and bowel, as future therapy for individuals with spinal cord injury, was examined using a rat model. The current study examined the feasibility of alternative routes of administration, which are more practical for clinical use than intravenous (IV) administration. Voiding and isovolumetric cystometry were recorded in anesthetized, acutely spinalized, female rats after IV, subcutaneous (SC), intramuscular (IM), intranasal (IN), or sublingual (SL) administration of [Lys 5 ,MeLeu 9 ,Nle 10 ]-NKA (4-10) (LMN-NKA). Administration of LMN-NKA (1-10μg/kg IV; 10-300μg/kg SC or IM; 15-1000μg/kg IN or 300-1500μg/kg SL) elicited rapid-onset, short-duration, dose-related increases in bladder pressure and voiding with the rank order for time of both onset and duration being IV < IN < SC = IM < SL. The incidence of voiding was dependent on the dose and route, with all routes resulting in a high voiding efficiency (~ 70%). Like LMN-NKA, neurokinin A (NKA 1-100μg/kg IV) and GR 64349 (0.1-30μg/kg IV or 1-300μg/kg SC) produced rapid-onset, short-duration increases in bladder pressure, as well as colorectal pressure. Administration of vehicle never produced bladder or rectal contractions or voiding. Transient hypotension was observed after IV injection of LMN-NKA, which was less pronounced after SC injection. Hypotension was not apparent with GR 64349. In conclusion, selective NK2 receptor agonists, administered through various non-IV routes of administration, may provide a safe, convenient, and efficacious method for inducing voiding., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU(K5) in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU(K5)-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLU(K5) antagonist described to date. Comparisons were made to the competitive GLU(K5)/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU(K5) receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 microM)-induced currents with an IC50 value of 0.045 +/- 0.011 microM. In HEK293 cells transfected with GLU(K5), GLU(K2)/GLU(K5), or GLU(K5)/GLU(K6) receptors, LY466195 produced IC50 values of 0.08 +/- 0.02, 0.34 +/- 0.17, and 0.07 +/- 0.02 microM, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID100 value of 100 microg/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 microg/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 microg/kg, respectively while having no N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.

Purpose: The purpose of the present study was to determine the peripheral neural pathways, spinal distribution, sizes, and peptide transmitter content of primary afferent and autonomic efferent neurons that innervate the prostate gland., Methods: Retrograde transport of the fluorescent dye "fast blue" (injected into the prostate gland) was combined with neurotransmitter immunohistochemistry. Lesions of the pelvic and pudendal nerve were used to determine the peripheral neural pathways., Results: The majority of the afferent innervation arose from the sacral dorsal root ganglia (DRG) and was equally comprised of small, substance P- and calcitonin gene-related peptide-immunoreactive (IR) neurons and large, non-IR neurons. The majority (70%) of the afferent axons traversed the pelvic nerve with the remainder traversing the pudendal nerve. Fewer afferent neurons were located in lumbar DRG; nearly all of these were small, peptidergic neurons. Efferent autonomic neurons were located in the inferior mesenteric ganglia (IMG), sympathetic chain ganglia (SCG), and pelvic plexus ganglia (PPG). Nearly all efferent neurons in the IMG and SCG, but only 2/3 of the PPG neurons, contained dopamine-beta-hydroxylase. Substantial neuropeptide Y innervation was derived from the SCG but not the IMG or PPG., Conclusions: First, clinical reports suggested that sensory innervation of the prostate would be purely nociceptive in nature (implied by small, peptide-IR neurons). However, the present study suggests that there may also be a substantial, presumably non-nociceptive, afferent innervation (implied by findings of large, non-IR neurons). Second, 3 sources of autonomic efferent innervation exist, each being different in the distribution of transmitter phenotypes. Understanding the physiological role of putative non-nociceptive primary afferent neurons, and the differential roles of the various autonomic neurons, is likely to be important in developing therapies for the treatment of prostatic diseases, such as benign prostatic hyperplasia and prostatodynia.