title: Brief Isolation Changes Nociceptive Behaviors and Compromises Drug Tests in Mice.
abstract: Herding with a litter is known to comfort rodents, whereas isolation and grouping with noncagemates provoke stress. The effects of stress induced by isolation and grouping with noncagemates on pain responses, and their underlying mechanisms remain elusive. We assessed the effect of isolation, a common condition during behavioral tests, and of grouping on defecation and pain behaviors of mice. Fecal pellets were counted 2 hours after exposure to the test chamber. It is significantly more in the isolated mice than in the grouped mice. Hindpaw withdrawal threshold and withdrawal latency were adopted as the indicatives of mechanical and thermal pain sensitivities, respectively. Interestingly, isolated mice showed higher pain thresholds than mice grouping with cagemates, and even those with noncagemates, indicating analgesic effects. Such effects were reduced by intrathecal injection of 0.01 mg/kg of naloxone (opioid receptor antagonist), atosiban (oxytocin and vasopressin receptor antagonist), and ketanserin (5-HT receptor antagonist). Intraperitoneal delivery of 1 mg/kg of naloxone and atosiban, but not ketanserin, also alleviated the isolation-induced analgesic effects. In contrast, these drugs at the same dose had no significant effect on the mice grouping with cagemates. In addition, the effect of morphine on thermal pain was more robust in the mice grouping with cagemates than in the isolated mice. These data demonstrated that brief isolation caused analgesia, mediated by endogenous opioidergic, oxytocinergic, and serotonergic pathways. These results indicate that isolation during pain behavioral tests can affect pain responses and the efficacy of drugs; thus, nociception tests should be conducted in grouping.
authors.affiliation: Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Rafael Taeho
authors.identifier: 0000-0002-0127-2396
authors.initials: RT
authors.lastname: Han
authors.affiliation: Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Hyunkyoung
authors.initials: H
authors.lastname: Lee
authors.affiliation: Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul, Korea.
authors.forename: JaeHee
authors.initials: J
authors.lastname: Lee
authors.affiliation: Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Sat-Byol
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Division of Biological Science and Technology, Science and Technology College, Yonsei University Wonju Campus, Wonju, Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutics and Biotechnology, College of Medical Engineering, Konyang University, Chungnam, Korea.
authors.forename: Seung Keun
authors.initials: SK
authors.lastname: Back
authors.affiliation: Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Heung Sik
authors.initials: HS
authors.lastname: Na
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005243:Feces; D006358:Hot Temperature; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D059226:Nociceptive Pain / Q000188:drug therapy* / Q000523:psychology*; D010147:Pain Measurement / Q000379:methods*; D017288:Pain Threshold / Q000187:drug effects* / Q000523:psychology*; D010812:Physical Stimulation; D012702:Serotonin Antagonists / Q000494:pharmacology; D012934:Social Isolation / Q000523:psychology*; D014668:Vasotocin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D012702:Serotonin Antagonists; C047046:atosiban; D009270:Naloxone; D009020:Morphine; D007650:Ketanserin; D014668:Vasotocin
keywords: analgesics; animal models; drug testing; isolation; pain assessment; pain behaviors; rodent