Abstract
Persistent pain affecting patients with inflammatory bowel diseases (IBDs) is still very difficult to treat. Carbonic anhydrase (CA) represents an intriguing pharmacological target considering the anti-hyperalgesic efficacy displayed by CA inhibitors in both inflammatory and neuropathic pain models. The aim of this work was to evaluate the effect of inhibiting CA IV, particularly when expressed in the gut, on visceral pain associated with colitis induced by 2,4-di-nitrobenzene sulfonic acid (DNBS) in rats. Visceral sensitivity was assessed by measuring animals’ abdominal responses to colorectal distension. Repeated treatment with the selective CA IV inhibitors AB-118 and NIK-67 effectively counteracted the development of visceral pain induced by DNBS. In addition to pain relief, AB-118 showed a protective effect against colon damage. By contrast, the anti-hyperalgesic activity of NIK-67 was independent of colon healing, suggesting a direct protective effect of NIK-67 on visceral sensitivity. The enzymatic activity and the expression of CA IV resulted significantly increased after DNBS injection. NIK-67 normalised CA IV activity in DNBS animals, while AB-118 was partially effective. None of these compounds influenced CA IV expression through the colon. Although further investigations are needed to study the underlying mechanisms, CA IV inhibitors are promising candidates in the search for therapies to relieve visceral pain in IBDs.
Highlights
Persistent abdominal pain is still an intractable problem in patients affected by inflammatory bowel diseases (IBDs)
IBD-related symptoms have been classically attributed to intestinal inflammation, 20–50% of patients develop a chronic syndrome characterised by pain, bloating and dysmotility, which persists after the remission of colitis [1,2,3]
The present work highlighted the involvement of Carbonic anhydrase (CA) IV in the development of visceral pain induced by colitis
Summary
Persistent abdominal pain is still an intractable problem in patients affected by inflammatory bowel diseases (IBDs). IBD-related symptoms have been classically attributed to intestinal inflammation, 20–50% of patients develop a chronic syndrome characterised by pain, bloating and dysmotility, which persists after the remission of colitis [1,2,3]. The complex nature of this type of pain makes patients partially responsive to anti-inflammatory drugs, anticonvulsants or antidepressants, which are classically used in the management of pain syndromes [4,5]. Recent advances in the identification and characterisation of novel drug targets have evidenced carbonic anhydrase inhibition as a new approach for designing novel painrelieving agents [6]. CAs are enzymes involved in various physiological reactions including respiration, pH regulation, Na+
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