Endothelin A receptor in nociceptors is essential for persistent mechanical pain in a chronic pancreatitis of mouse model.

Abstract

Background: Chronic pancreatitis (CP) accompanied with persistent abdominal pain represents a major clinical challenge for the symptom management in patients. Although with clear involvement of neuropathy, the detailed mechanisms underlying pain hypersensitivity associated with CP are not totally clear. The endothelin system has been reported to contribute to chronic pain and chronic inflammatory settings, and is a potential therapeutic target for the treatment of chronic pain.

Aim: To evaluate the role of nociceptor-specific endothelin A receptor (ETAR) in pain hypersensitivity in a CP mouse model and its potential contributing mechanisms.

Methods: Oral gavage delivery of dibutyltin dichloride (DBTC) was used to induce CP in mice. A conditional knockout (CKO) strain which specifically delete ETAR in dorsal root ganglion (DRG) nociceptive neurons was generated. Abdominal pain hypersensitivity associated with CP and other behaviors were evaluated. The size of mouse gallbladder was measured and pancreatic histopathology was examined to validate the CP model. Calcitonin gene-related peptide expression and immune cells in the innervated DRGs and spinal cord were also examined. Calcium imaging in dissociated DRG neurons was performed to investigate the excitability of affected nociceptive neurons.

Results: Specific deletion of endothelin receptor type A gene in nociceptive DRG neurons did not affect basal abdominal thermal and mechanical pain threshold in mice. Abdominal mechanical pain hypersensitivity was persistent in DBTC-treated WT mice but was significantly reduced in DBTC-treated CKO mice. DBTC treatment did not affect mouse nociceptive responses to heat and cold stimuli, as well as motor functions and anxiety-like behaviors of mice. DBTC treatment induced severe pancreatic inflammation and obvious gallbladder enlargement in wild type (WT) mice, but less in CKO mice. DBTC-induced increase of calcitonin gene-related peptide- and induction of brown adipocytes 1-positive signals in the DRG and spinal cord in WT mice were remarkably attenuated in CKO mice. DRG neurons from CKO mice exhibited less excitability and sensitivity in response to endothelin-1 exposure than those from WT mice.

Conclusion: DBTC intragastric administration in mice produced a convenient and reliable animal model for studying abdominal pain associated with CP. ETAR-dependent endothelin signaling in nociceptors is important for the development of persistent abdominal mechanical hypersensitivity in mice.