title: Synergistic effect of 5-hydroxytryptamine 3 and neurokinin 1 receptor antagonism in rodent models of somatic and visceral pain.
abstract: Synergistic activity has been observed between serotonergic 5-hydroxytryptamine 3 (5-HT3) and tachykinergic neurokinin 1 (NK1) receptor-mediated responses. This study investigated the efficacy of a 5-HT3 antagonist, palonosetron, and a NK1 antagonist, netupitant, alone or in combination in rodent models of somatic and visceral colonic hypersensitivity. In a rat model of experimental neuropathic pain, somatic hypersensitivity was quantified by the number of ipsilateral paw withdrawals to a von Frey filament (6g). Electrophysiologic responses were recorded in the dorsal horn neurons after mechanical or thermal stimuli. Acute colonic hypersensitivity was induced experimentally in rats by infusing dilute acetic acid (0.6%) directly into the colon. Colonic sensitivity was assessed by a visceromotor behavioral response quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mm Hg) of colorectal distension. Palonosetron or netupitant was administered alone or in combination via oral gavage. When dosed alone, both significantly reduced somatic sensitivity, decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation, and caused significant (P < 0.05) inhibition of colonic hypersensitivity in a dose-dependent manner. The combined administration of palonosetron and netupitant at doses that were ineffective alone significantly reduced both somatic and visceral sensitivity and decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation. In summary, the combination of palonosetron with a NK1 receptor antagonist showed synergistic analgesic activity in rodent models of somatic and visceral hypersensitivity, and may prove to be a useful therapeutic approach to treat pain associated with irritable bowel syndrome.
authors: Department of Physiology (B.G.-V.M.), Veterans Affairs Medical Center (B.G.-V.M.), Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center (B.G.-V.M., E.M., K.T.), Oklahoma City, Oklahoma; Research and Preclinical Department, Helsinn Healthcare SA, Lugano, Switzerland (C.P.); and Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom (L.A.B., A.D.).
authors: Beverley
authors: B
authors: Greenwood-Van Meerveld
authors: Department of Physiology (B.G.-V.M.), Veterans Affairs Medical Center (B.G.-V.M.), Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center (B.G.-V.M., E.M., K.T.), Oklahoma City, Oklahoma; Research and Preclinical Department, Helsinn Healthcare SA, Lugano, Switzerland (C.P.); and Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom (L.A.B., A.D.).
authors: Ehsan
authors: E
authors: Mohammadi
authors: Department of Physiology (B.G.-V.M.), Veterans Affairs Medical Center (B.G.-V.M.), Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center (B.G.-V.M., E.M., K.T.), Oklahoma City, Oklahoma; Research and Preclinical Department, Helsinn Healthcare SA, Lugano, Switzerland (C.P.); and Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom (L.A.B., A.D.).
authors: Karl
authors: K
authors: Tyler
authors: Department of Physiology (B.G.-V.M.), Veterans Affairs Medical Center (B.G.-V.M.), Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center (B.G.-V.M., E.M., K.T.), Oklahoma City, Oklahoma; Research and Preclinical Department, Helsinn Healthcare SA, Lugano, Switzerland (C.P.); and Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom (L.A.B., A.D.) claudio.pietra@helsinn.com.
authors: Claudio
authors: C
authors: Pietra
authors: Department of Physiology (B.G.-V.M.), Veterans Affairs Medical Center (B.G.-V.M.), Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center (B.G.-V.M., E.M., K.T.), Oklahoma City, Oklahoma; Research and Preclinical Department, Helsinn Healthcare SA, Lugano, Switzerland (C.P.); and Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom (L.A.B., A.D.) claudio.pietra@helsinn.com.
authors: Lucy A
authors: LA
authors: Bee
authors: Department of Physiology (B.G.-V.M.), Veterans Affairs Medical Center (B.G.-V.M.), Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center (B.G.-V.M., E.M., K.T.), Oklahoma City, Oklahoma; Research and Preclinical Department, Helsinn Healthcare SA, Lugano, Switzerland (C.P.); and Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom (L.A.B., A.D.).
authors: Anthony
authors: A
authors: Dickenson
mesh_terms: D000200:Action Potentials; D000284:Administration, Oral; D000818:Animals; D003106:Colon / Q000294:innervation; D004338:Drug Combinations; D004357:Drug Synergism; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D059226:Nociceptive Pain / Q000188:drug therapy*; D000077924:Palonosetron; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D059265:Visceral Pain / Q000188:drug therapy*; D010879:Piperazines; D044482:Benzeneacetamides
chemical_list: D004338:Drug Combinations; D007546:Isoquinolines; D064729:Neurokinin-1 Receptor Antagonists; D000077924:Palonosetron; D011725:Pyridines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; C508854:netupitant; D010879:Piperazines; D044482:Benzeneacetamides