Papers of the Week

Painful bladder syndrome and irritable bowel syndrome affect 10%-15% of the global population. Current treatment options for these syndromes are ineffective in severe disease progression and are fraught with adverse effects. Prolonged use of conventional opioids causes constipation, respiratory depression, tolerance, and addiction. Bifunctional opioid ligands with mixed agonist/antagonist profiles at 2 types of opioid receptors (ORs) possess therapeutic advantages. Eluxadoline (ELX, Viberzi), a drug for diarrhea-predominant irritable bowel syndrome, has an agonistic effect on μ-opioid receptor (MOR) and an antagonistic effect on δ-opioid receptor (DOR). ELX alleviates pain and normalizes peristalsis by activating MOR without causing constipation, a DOR antagonistic effect. However, its mechanism of analgesic action is not known. We investigated the analgesic mechanism of ELX in colon and bladder pain by recording the visceromotor responses (VMRs) to painful distension of the organ and identified the site of action of the drug in pain signaling pathways. ELX inhibited VMRs via the activation of spinal MOR. The peripherally restricted MOR antagonist naloxone-methiodide (meth-NLX) did not reverse the VMR inhibition by ELX, whereas centrally acting NLX reversed it. ELX did not inhibit the excitation of mechanosensitive afferent fibers in lumbar 6 (L6) and sacral 1 (S1) dorsal root innervating the bladder or colon. In contrast, ELX inhibited excitation of bladder distension-responsive L6 and S1 spinal neurons. The inhibition was reversed by NLX, but not by meth-NLX. Electrophysiology results reinforce behavioral experiments suggesting that ELX produces analgesia by attenuating responses of spinal neurons, but not visceral sensory afferents. SIGNIFICANCE STATEMENT: The bifunctional opioid ligand eluxadoline is an FDA-approved drug for the treatment of diarrhea-predominant irritable bowel syndrome to normalize bowel movement and to relieve abdominal pain. This study documents for the first time to our knowledge that unlike its peripheral action to normalize diarrhea, the drug alleviates colon and bladder pain centrally by modulating responses of lumbo-sacral (L6-S1) spinal neurons.