(P155) TOWARDS DEVELOPMENT OF TARGETED THERAPEUTICS FOR CHRONIC PAIN IN IBD: ANALGESIC EFFICACY OF AN ORAL GCPII INHIBITOR IN PRECLINICAL VISCERAL PAIN MODELS

Background: Abdominal pain is a frequent symptom occurring in patients with inflammatory bowel disease (IBD), and, unfortunately, as many as 50% of patients in endoscopic remission experience persistent chronic pain. Despite this high prevalence, no targeted therapeutics are available to manage pain in IBD. Agents including acetaminophen, non-steroidal anti-inflammatory medications (NSAIDs) and opioids remain in high utilization, despite their known adverse gastrointestinal side effect profiles and, in some cases, limited analgesic efficacy. Glutamate carboxypeptidase II (GCPII) is upregulated in IBD, where it may be a unique therapeutic target for pain management. GCPII is a membrane-associated zinc metallopeptidase capable of regulating glutamatergic neurotransmission; Excess GCPII activity has been implicated in numerous pain disorders, including neuropathic pain and cancer-associated pain, where its inhibition is analgesic in preclinical models.  However, GCPII has not yet been examined in the context of visceral pain.

Hypotheses:  GCPII will be upregulated in rodent models of post-inflammatory chronic visceral hypersensitivity (CVH) and treatment with oral, gut-restricted, GCPII inhibitor (S)-IBD3540 will be analgesic.

Method: Oral GCPII inhibitor (S)-IBD3540 was evaluated in 2 murine models of post-inflammatory, chronic visceral hypersensitivity (CVH): acetic acid-induced CVH of neonatal mice and TNBS-induced CVH of adult mice. In each model, (S)-IBD3540 (2.75 – 275 mg/kg) was administered once daily for 7 days preceding measurement of abdominal visceromotor response (VMR) to graded colorectal distension (CRD) (n=5-7/group). Alongside functional measurements, MPO ELISA and GCPII immunohistochemistry were performed to validate absence of inflammation and quantify colon mucosal GCPII expression.

Results: Oral (S)-IBD3540 treatment was significantly analgesic in both models, attenuating hyperalgesia to baseline at doses as low as 2.75 mg/kg, and displaying comparable efficacy to oral gabapentin (2-way ANOVA with Holm-Šídák multiple comparisons test). MPO ELISA confirmed absence of active inflammation at the time of VMR/CRD measurement. Mucosal GCPII expression was found to be significantly increased in both models (2-tailed t-test; TNBS-CVH, p=0.0044; AA-CVH, p=0.0063).

Conclusions: There is a large unmet clinical need for chronic pain management in IBD. Here, we provide encouraging preclinical evidence that inhibition of GCPII has potent analgesic effects in relevant rodent models of post-inflammatory visceral pain. Studies interrogating GCPII dysregulation in biopsies of IBD patients experiencing chronic pain in IBD are actively ongoing within our laboratory.