Artemin Immunotherapy Is Effective in Preventing and Reversing Cystitis-Induced Bladder Hyperalgesia via TRPA1 Regulation

• We determined whether treatment with an artemin sequestering antibody (α-ARTN) affected cyclophosphamide-induced bladder hyperalgesia and bladder primary afferent function.
• α-ARTN effectively blocked the development of bladder hyperalgesia and reversed hyperalgesia once it was established.
• α-ARTN normalized noxious bladder distension–induced spinal expression of phospho-ERK1/2 immunoreactivity.
• Calcium imaging experiments of bladder afferents using mustard oil indicate that ARTN may regulates neuronal function via TRPA1.
• α-ARTN may be an effective therapeutic strategy for individuals suffering from interstitial cystitis–related bladder pain.

Injury- or disease-induced artemin (ARTN) signaling can sensitize primary afferents and contribute to persistent pain. We demonstrate that administration of an ARTN neutralizing antibody, anti-artemin (α-ARTN), can block the development of, and reverse already established, bladder hyperalgesia associated with cyclophosphamide-induced cystitis in mice. We further demonstrate that α-ARTN therapy blocks upregulation of TRPA1, an ion channel contributing to persistent bladder pain during cyclophosphamide-induced cystitis, and decreases phospho-ERK1/2 immunoreactivity in regions of the spinal cord receiving bladder afferent input. Thus, α-ARTN is a promising novel therapeutic approach for treatment of bladder hyperalgesia that may be associated with interstitial cystitis/painful bladder syndrome, as well as cystitis associated with antitumor or immunosuppressive cyclophosphamide therapy.Perspectiveα-ARTN therapy effectively prevented and reversed ongoing bladder hyperalgesia in an animal model of cystitis, indicating its potential as an efficacious treatment strategy for ongoing bladder pain associated with interstitial cystitis/painful bladder syndrome.