Involvement of the cystathionine-γ-lyase/Cav3.2 pathway in substance P-induced bladder pain in the mouse, a model for nonulcerative bladder pain syndrome

Tsubota, Maho; Okawa, Yasumasa; Irie, Yoshihito; Maeda, Mariko; Ozaki, Tomoka; Sekiguchi, Fumiko; Ishikura, Hiroyasu; Kawabata, Atsufumi

doi:10.1016/j.neuropharm.2018.01.037

Cited by 12 publications

(5 citation statements)

References 24 publications

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“…Bladder nerve grow factor (NGF) and substance P are also reported to be involved in bladder pain [27, 28]. The role (if any) of MIF in modulating NGF or Substance P is not known and was not investigated in the present study.…”

Section: Discussionmentioning

confidence: 98%

MIF mediates bladder pain, not inflammation, in cyclophosphamide cystitis

Kouzoukas

Meyer-Siegler

et al. 2019

Cytokine: X

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Macrophage migration inhibitory factor (MIF), a proinflammatory mediator, is recognized as a player in inflammatory and neuropathic pain. Cyclophosphamide (CYP) results in bladder inflammation and pain and it’s a frequently used animal model of interstitial cystitis/bladder pain syndrome (IC/BPS). Because pretreatment with a MIF inhibitor (ISO-1) prevented both CYP-induced bladder pain and inflammation we used genetic MIF knockout (KO) mice to further investigate MIF’s role in CYP-induced bladder pain and inflammation. Abdominal mechanical threshold measured bladder pain induced by CYP in wild type (WT) and MIF KO mice at several time points (0–48 hours). End-point (48 hours) changes in micturition parameters and histological signs of bladder inflammation were also evaluated. Abdominal mechanical hypersensitivity developed within 4 hours after CYP injection (and lasted for the entire observation period: 48 hours) in WT mice. MIF KO mice, on the other hand, did not develop abdominal mechanical hypersensitivity suggesting that MIF is a pivotal molecule in mediating CYP-induced bladder pain. Both WT and MIF KO mice treated with CYP showed histological signs of marked bladder inflammation and showed a significant decrease in micturition volume and increase in frequency. Since both changes were blocked in MIF KO mice by pretreatment with a MIF inhibitor (ISO-1) it is likely these are non-specific effects of ISO-1. MIF mediates CYP-induced bladder pain but not CYP-induced bladder inflammation. The locus of effect (bladder) or central (spinal) for MIF mediation of bladder pain remains to be determined.

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Section: Discussionmentioning

confidence: 98%

MIF mediates bladder pain, not inflammation, in cyclophosphamide cystitis

Kouzoukas

Meyer-Siegler

et al. 2019

Cytokine: X

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“…In the present study, we focused on SP. Even though SP involvement has been reported in the context of cystitis manifestation and exacerbation [ 6 , 7 , 19 , 20 ], the effect of YKS on SP secretion remains unclear. Thus, in this study, we investigated the expression of SP in the bladder wall and spinal dorsal horn, and the influence of YKS on SP.…”

Section: Discussionmentioning

confidence: 99%

“…We reported that the antioxidant effect of YKS is one of the mechanisms involved in the analgesic effect of YKS on HIC pain [ 18 ]. In the present study, we focused on the excessive expression of SP in the bladder wall and spinal dorsal horn as potential causes of bladder pain [ 19 , 20 ], and examined the impact of YKS on SP secretion.…”

Section: Introductionmentioning

confidence: 99%

Analgesic Effect of the Kampo Formula Yokukansan via the Suppression of Substance P in an Experimental Rat Model of Hunner-Type Interstitial Cystitis

Tsunokawa,

Tsukada,

Inoue

et al. 2024

Cureus

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Introduction: Yokukansan (YKS), a Kampo formula used in traditional Japanese medicine, has an analgesic effect, and is used for various pain disorders. This study investigated its analgesic effects on Hunner-type interstitial cystitis (HIC) and its mechanism of action in animal models. Methods: Rats with toll-like receptor-7 agonist (loxoribine)-induced HIC were used. Eight-week-old female Wistar rats were divided into three groups: control, HIC, and HIC-administered YKS (YKS + HIC). Bladder pain was assessed based on escape behavior using the von Frey test. Three days after HIC induction, the bladder and spinal cord were excised, and the expression of substance P (SP) was examined. Results: The pain threshold decreased significantly in the HIC group compared to that in the control group, but this decrease was suppressed by further YKS administration. The expression of SP in the bladder wall and spinal cord increased significantly in the HIC group compared to that in the control group; however, this increase was suppressed by YKS administration. Conclusion: SP is involved in the onset of bladder pain via neurokinin 1 receptors in bladder tissue. YKS may be useful for managing HIC-induced pain, and the suppression of SP secretion is one of its mechanisms of action.

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“…Several anti‐epileptic drugs including ethosuximide are thought to act in part through the inhibition of T‐type channels (Weiss & Zamponi, 2019 ), and interestingly, these same T‐type targeting clinical compounds have analgesic effects in rodents (Dogrul et al, 2003 ; Flatters & Bennett, 2004 ). More broadly, selective knockdown or block of T‐type channels through genetic and pharmacological approaches reverses pain hypersensitivity in rodent models of pain including bladder pain (Tsubota et al, 2018 ), post‐surgical pain (Joksimovic et al, 2019 ), inflammatory pain (Watanabe et al, 2015 ), nerve injury‐induced pain (Bourinet et al, 2005 ; Feng et al, 2019 ) and chemotherapy‐induced and diabetic peripheral neuropathies (Jacus et al, 2012 ; Li et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The T‐type calcium channel antagonist, Z944, reduces spinal excitability and pain hypersensitivity

Harding

Dedek

Bonin

et al. 2021

British J Pharmacology

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Background and Purpose: T-type voltage-gated calcium channels are an emerging therapeutic target for neurological disorders including epilepsy and pain. Inhibition of T-type channels reduces the excitability of peripheral nociceptive sensory neurons and reverses pain hypersensitivity in male rodent pain models. However, administration of peripherally restricted T-type antagonists failed to show efficacy in multiple clinical and preclinical pain trials, suggesting that inhibition of peripheral T-type channels alone may be insufficient for pain relief. Experimental Approach: We utilized the selective and CNS-penetrant T-type channel antagonist, Z944, in electrophysiological, calcium imaging and behavioural paradigms to determine its effect on lamina I neuron excitability and inflammatory pain behaviours. Key Results: Voltage-clamp recordings from lamina I spinal neurons of adult rats revealed that approximately 80% of neurons possess a low threshold T-type current, which was blocked by Z944. Due to this highly prevalent T-type current, Z944potently blocked action-potential evoked somatic and dendritic calcium transients in lamina I neurons. Moreover, application of Z944 to spinal cord slices attenuated action potential firing rates in over half of laminae I/II neurons. Finally, we found that intraperitoneal injection of Z944 (1-10 mgÁkg À1 ) dose-dependently reversed mechanical allodynia in the complete Freund's adjuvant model of persistent inflammatory pain, with a similar magnitude and time course of analgesic effects between male and female rats. Conclusion and Implications:T-type calcium channels critically shape the excitability of lamina I pain processing neurons and inhibition of these channels by the clinical stage antagonist Z944 potently reverses pain hypersensitivity across sexes.

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Involvement of the cystathionine-γ-lyase/Cav3.2 pathway in substance P-induced bladder pain in the mouse, a model for nonulcerative bladder pain syndrome

Cited by 12 publications

References 24 publications

MIF mediates bladder pain, not inflammation, in cyclophosphamide cystitis

MIF mediates bladder pain, not inflammation, in cyclophosphamide cystitis

Analgesic Effect of the Kampo Formula Yokukansan via the Suppression of Substance P in an Experimental Rat Model of Hunner-Type Interstitial Cystitis

The T‐type calcium channel antagonist, Z944, reduces spinal excitability and pain hypersensitivity

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