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Mechanisms of inhibitory action of TRK-130 (Naltalimide), a μ-opioid receptor partial agonist, on the micturition reflex

  • Urology - Original Paper
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Abstract

Purpose

To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex.

Methods

The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats.

Results

TRK-130 (0.001–0.01 mg/kg, iv) dose-dependently inhibited RBCs, which was dose-dependently antagonized by naloxone; however, the antagonism susceptibility was different from morphine (1 mg/kg, iv). The minimum effective dose (0.003 mg/kg) of TRK-130 remained similar in spinal cord-transected animals. TRK-130 (0.0025 mg/kg, iv) increased bladder capacity without changing the voiding efficiency, maximum flow rate, and intravesical pressure at the maximum flow rate, whereas oxybutynin (1 mg/kg, iv) increased the bladder capacity but affected the other parameters. TRK-130 (0.005 mg/kg, iv) did not produce significant changes on the bladder contractions induced by peripheral stimulation of the pelvic nerve, while oxybutynin (1 mg/kg, iv) significantly suppressed the bladder contractions.

Conclusions

These results suggest that TRK-130 enhances the bladder storage function by modulating the afferent limb of the micturition reflex through µ-opioid receptors in the spinal cord. TRK-130 could be a more effective and safer therapeutic agent with a different fashion from antimuscarinics and conventional opioids for overactive bladder.

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References

  1. Wein AJ (2003) Diagnosis and treatment of the overactive bladder. Urology 62:20–27

    Article  PubMed  Google Scholar 

  2. Wein AJ, Rackley RR (2006) Overactive bladder: a better understanding of pathophysiology, diagnosis and management. J Urol 175:S5–S10

    Article  PubMed  Google Scholar 

  3. Cipullo LMA, Cosimato C, Filippelli A, Conti V, Izzo V, Zullo F, Guida M (2014) Pharmacological approach to overactive bladder and urge urinary incontinence in women: an overview. Eur J Obstet Gynecol Reprod Biol 174:27–34

    Article  CAS  PubMed  Google Scholar 

  4. Brostrøm S, Hallas J (2009) Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 65:309–314

    Article  PubMed  Google Scholar 

  5. Sexton CC, Notte SM, Maroulis C, Dmochowski RR, Cardozo L, Subramanian D, Coyne KS (2011) Persistence and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a systematic review of the literature. Int J Clin Pract 65:567–585

    Article  CAS  PubMed  Google Scholar 

  6. Chancellor MB, Migliaccio-Walle K, Bramley TJ, Chaudhari SL, Corbell C, Globe D (2013) Long-term patterns of use and treatment failure with anticholinergic agents for overactive bladder. Clin Ther 35:1744–1751

    Article  CAS  PubMed  Google Scholar 

  7. Nitti VW, Khullar V, van Kerrebroeck P, Herschorn S, Cambronero J, Angulo JC, Blauwet MB, Dorrepaal C, Siddiqui E, Martin NE (2013) Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract 67:619–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dray A, Metsch R (1984) Inhibition of urinary bladder contractions by a spinal action of morphine and other opioids. J Pharmacol Exp Ther 231:254–260

    CAS  PubMed  Google Scholar 

  9. Soulard C, Pascaud X, Roman FJ, Grouhel A, Junien JL (1992) Pharmacological evaluation of JO 1870: relation to the potential treatment of urinary bladder incontinence. J Pharmacol Exp Ther 260:1152–1158

    CAS  PubMed  Google Scholar 

  10. Fujimura M, Izumimoto N, Momen S, Yoshikawa S, Kobayashi R, Kanie S, Hirakata M, Komagata T, Okanishi S, Hashimoto T, Yoshimura N, Kawai K (2014) Characteristics of TRK-130 (Naltalimide), a novel opioid ligand, as a new therapeutic agent for overactive blaidder. J Pharmacol Exp Ther 350:543–551

    Article  PubMed  Google Scholar 

  11. Doi T, Kamo I, Imai S, Okanishi S, Ikeura Y, Natsugari H (2000) Effects of TAK-637, a tachykinin receptor antagonist, on the micturition reflex in guinea pigs. Eur J Pharmcol 395:241–246

    Article  CAS  Google Scholar 

  12. Nagabukuro H, Okanishi S, Doi T (2004) Effects of TAK-802, a novel acetylcholinesterase inhibitor, and various cholinomimetics on the urodynamic characteristics in anesthetized guinea pigs. Eur J Pharmcol 494:225–232

    Article  CAS  Google Scholar 

  13. Morikawa K, Hashimoto S, Yamauchi T, Kato H, Ito Y, Gomi Y (1992) Inhibitory effect of inaperisone hydrochloride (inaperisone), a new centrally acting muscle relaxant, on the micturition reflex. Eur J Pharmacol 213:409–415

    Article  CAS  PubMed  Google Scholar 

  14. Pasternak GW, Wood PJ (1986) Multiple mu opiate receptors. Life Sci 38:1889–1898

    Article  CAS  PubMed  Google Scholar 

  15. Pasternak GW (2001) Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends Pharmacol Sci 22:67–70

    Article  CAS  PubMed  Google Scholar 

  16. Bolan EA, Pan YX, Pasternak GW (2004) Functional analysis of MOR-1 splice variants of the mouse mu opioid receptor gene Oprm. Synapse 51:11–18

    Article  CAS  PubMed  Google Scholar 

  17. Lee LM, Lin CS, Chung HH, Lin KC, Cheng JT (2012) Urinary bladder relaxation through activation of opioid µ-receptors induced by loperamide is increased in diabetic rats. Exp Clin Endocrinol Diabetes 120:323–328

    CAS  PubMed  Google Scholar 

  18. Sakurada S, Hayashi T, Yuhki M, Fujimura T, Murayama K, Yonezawa A, Sakurada C, Takeshita M, Zadina JE, Kastin AJ, Sakurada T (2000) Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone. Brain Res 881:1–8

    Article  CAS  PubMed  Google Scholar 

  19. Sakurada S, Hayashi T, Yuhki M, Fujimura T, Murayama K, Yonezawa A, Sakurada C, Takeshita M, Sato T, Zadina JE, Kastin AJ, Sakurada T (2002) Differential antagonism of endomorphin-1 and endomorphin-2 supraspinal antinociception by naloxonazine and 3-methoxynaltrexone. Peptides 23:895–901

    Article  CAS  PubMed  Google Scholar 

  20. Dou XL, Qin RL, Qu J, Liao YH, Lu YC, Zhang T, Shao C, Li YQ (2013) Synaptic connections between endomorphin 2-immunoreactive terminals and µ-opioid receptor-expressing neurons in the sacral parasympathetic nucleus of the rat. PLoS ONE 8:e62028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Soergel DG, Subach RA, Burnham N, Lark MW, James IE, Sadler BM, Skobieranda F, Violin JD, Webster LR (2014) Biased agonism of the µ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain 155:1829–1835

    Article  CAS  PubMed  Google Scholar 

  22. Dray A, Metsch R (1984) Morphine and the centrally-mediated inhibition of urinary bladder motility in the rat. Brain Res 297:191–195

    Article  CAS  PubMed  Google Scholar 

  23. Dray A, Metsch R (1984) Opioid receptor subtypes involved in the central inhibition of urinary bladder motility. Eur J Pharmacol 104:47–53

    Article  CAS  PubMed  Google Scholar 

  24. Gouarderes C, Cros J, Quirion R (1985) Autoradiographic localization of mu, delta and kappa opioid receptor binding sites in rat and guinea pig spinal cord. Neuropeptides 6:331–342

    Article  CAS  PubMed  Google Scholar 

  25. Van Asselt E, Groen J, Van Mastrigt R (1995) A comparative study of voiding in rat and guinea pig: simultaneous measurement of flow rate and pressure. Am J Physiol 269:R98–R103

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan

    Morihiro Fujimura, Naoki Izumimoto, Sayoko Kanie, Ryosuke Kobayashi, Satoru Yoshikawa, Shinobu Momen, Mikito Hirakata, Toshikazu Komagata & Koji Kawai

  2. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan

    Satoshi Okanishi, Masashi Iwata, Tadatoshi Hashimoto & Takayuki Doi

  3. Departments of Urology and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Naoki Yoshimura

Authors
  1. Morihiro Fujimura
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  2. Naoki Izumimoto
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  3. Sayoko Kanie
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  4. Ryosuke Kobayashi
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  5. Satoru Yoshikawa
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  6. Shinobu Momen
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  7. Mikito Hirakata
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  8. Toshikazu Komagata
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  9. Satoshi Okanishi
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  10. Masashi Iwata
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  11. Tadatoshi Hashimoto
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  12. Takayuki Doi
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  13. Naoki Yoshimura
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  14. Koji Kawai
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Corresponding author

Correspondence to Morihiro Fujimura.

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Conflict of interest

Fujimura, Izumimoto, Kanie, Kobayashi, Yoshikawa, Momen, Hirakata, Komagata, and Kawai are employees of Toray Industries, Inc. Okanishi, Iwata, Hashimoto, and Doi are employees of Takeda Pharmaceutical Company Limited. Prof. Yoshimura received consulting fee from Toray Industries, Inc.

Ethical approval

All the animal experiments in this study were approved by the Animal Ethics Committee of the Research & Development Division, Toray, or Experimental Animal Care and Use Committee of Takeda.

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Fujimura, M., Izumimoto, N., Kanie, S. et al. Mechanisms of inhibitory action of TRK-130 (Naltalimide), a μ-opioid receptor partial agonist, on the micturition reflex. Int Urol Nephrol 49, 587–595 (2017). https://doi.org/10.1007/s11255-017-1509-y

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  • DOI: https://doi.org/10.1007/s11255-017-1509-y

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