Endogenous H₂S sensitizes PAR4-induced bladder pain

Area of Science:

• Biochemistry
• Physiology
• Pharmacology

Background:

• Bladder pain, a key symptom of interstitial cystitis/painful bladder syndrome, is linked to hydrogen sulfide (H2S) production.
• H2S, generated by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), plays a role in bladder hypersensitivity.

Purpose of the Study:

• To investigate the involvement of the H2S pathway in protease-activated receptor 4 (PAR4)-induced bladder pain.
• To elucidate the role of H2S in mediating referred bladder pain through macrophage migration inhibitory factor (MIF).

Main Methods:

• A mouse model of bladder pain was induced using intravesical instillation of a PAR4-activating peptide.
• H2S pathway involvement was assessed using enzyme inhibitors (d,l-propargylglycine, aminooxyacetic acid) and an H2S donor (NaHS).
• Evaluations included CBS, CSE, MIF expression, bladder function, inflammation, H2S production, and pain assessments in vivo and in vitro (SV-HUC-1 cells).

Main Results:

• H2S signaling and H2S-generating enzyme activity were upregulated in PAR4-induced bladder pain models.
• Inhibition of H2S production (AOAA) reduced pain, while H2S supplementation (NaHS) exacerbated it.
• AOAA increased MIF levels, while NaHS decreased them, suggesting MIF's role in H2S-mediated pain.

Conclusions:

• Endogenous H2S, produced by CBS or CSE, contributes to referred hyperalgesia in PAR4-induced bladder pain.
• This H2S-mediated pain is associated with MIF and occurs without significant bladder inflammation or altered micturition.
• The findings highlight H2S as a potential therapeutic target for bladder pain conditions.