Anesthesiology 2006; 104:1257– 65 © 2006 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Parturition in the Rat A Physiological Pain Model Gwe ´ nae ¨ lle Catheline, Ph.D.,* Bastien Touquet, Sc.B.,† Jean-Marie Besson, Ph.D.,‡ Marie-Christine Lombard, Ph.D.‡ Background: Pain during labor is a common and severe phenomenon, but its clinical management remains haphazard because its neurophysiology is poorly understood. In the cur- rent study, the authors evaluate the parturient rat as a relevant model to study the pharmacology of labor pain. Methods: Control of birth timing in term pregnant rats was achieved by gavage with RU 486 (5 mg/kg) the day before the expected day of parturition. The behavioral events preceding the expulsion of the first pup were analyzed, and immunode- tection of the c-Fos protein was used to evaluate the spinal neuronal activity at the lumbosacral level where genital and perineal inputs terminate. Results: Hind limb and abdominal stretches occurred during labor (mean number, 57  10), arbitrarily defined as the time elapsed between the first stretch and the expulsion of the first pup (mean duration, 62  5 min). Subcutaneous oxytocin in- creased the frequency of stretches, accounting for the fact that these manifestations are linked to uterine contractions. Finally, epidural morphine (30 g/10 l) in oxytocin-treated rats, al- though resulting in no change of labor duration, significantly decreased the number of stretches (8  2 vs. 57  12 for epidural saline) and the number of c-Fos–positive neurons in the lumbosacral spinal segments (80  25 vs. 165  17 for epidural saline). Conclusions: These results indicate that stretches during labor in the rat correspond to a behavioral response to noci- ception associated with uterine contractions and suggest that parturition in the rat could be a relevant model to investigate nociceptive mechanisms associated with parturition in women. PHYSIOLOGIC functions are generally painless. There is an exception for women regarding the reproductive tract; menstrual pain is common, but the most painful event occurs during labor at parturition. According to Bonica’s survey of 2,700 parturient women, 1 15% re- ported no or little pain, 35% reported moderate pain, 30% reported intense pain, and 20% reported very in- tense pain. In women, labor has been divided into three stages. The first one starts with the appearance of weak but regular uterine contractions; as the intensity of con- tractions increases, distension, stretching, and tearing of the lower uterine segment and the cervix becoming stronger and produce visceral pain with afferent infor- mations traveling by the hypogastric and pelvic nerves. The second stage of labor, the expulsion phase, is de- scribed as the most painful stage and results from dis- tension of the cervix, added to pressure applied on the pelvis and perineum, innervated by the pudendal nerve. The third stage of labor, the delivery, consists of the expulsion of the placenta and is not painful. Labor pain can be reduced by the use of local anesthetic and opi- oids. 2,3 An anesthetic method that could provide excel- lent analgesia with no adverse effects on the course of labor is an ideal goal that has not been achieved. 4,5 As in other areas of pain research, 6 the use of an appropriate animal model is a necessary step to achieve this goal and to elucidate the underlying neurophysio- logic and neuropharmacologic mechanisms of pain dur- ing parturition. Most studies using animals concern en- docrine modifications associated with gestation and parturition, 7–10 but studies of pain associated with this process are rare. 11,12 The aim of the current study was to evaluate the parturient rat as a model of physiologic pain. We first made behavioral observations during the period preceding the expulsion of the first pup. In the same rats, we then studied the parturition-induced activ- ity of spinal neurons receiving afferents of female repro- ductive tract and perineal sphere, using immunodetec- tion of c-Fos protein, which is an indirect indicator of noxiously activated spinal neurons. 13 Because labor pain is associated with uterine contractions in women, 1 we analyzed the effects of the well-known uterotonic sub- stance oxytocin 14,15 on behavioral manifestations ob- served during labor. Finally, we evaluated the analgesic potency of epidural morphine to assess the nociceptive component of the behavioral manifestation and spinal c-Fos expression observed at parturition. Materials and Methods This study, including care of the animals involved, was conducted according to the official edict presented by the French Ministry of Agriculture (Paris, France) and the recommendations of the Helsinki Declaration. There- fore, these experiments were conducted in an autho- rized laboratory and under the supervision of authorized researchers (G.C., M.-C.L., and J.-M.B.). Animals Experiments used primipara (310 – 400 g) and virgin (235–270 g) albino Sprague-Dawley female rats (Charles River, France; n = 62), purchased at gestation day 15 and arriving 1 week before the beginning of the exper- * Senior Lecturer, † Technician, ‡ Professor. Received from Ecole Pratique des Hautes Etudes, Laboratoire de Neurobiolo- gie Inte ´grative et Adaptative INSERM U378, Bordeaux, France. Submitted for publication July 12, 2005. Accepted for publication February 3, 2006. Supported by a grant from l’Institut UPSA de la Douleur, Rueil Malmaison, France. Dr. Catheline was supported by a grant attributed by the Fondation Pour la Recher- che Me ´dicale, Paris, France. Presented at the 5 e `me colloque de la Socie ´te ´ des Neurosciences, Toulouse, France, May 28 –31, 2001. Address correspondence to Dr. Catheline: Institut Franc ¸ois Magendie, Univer- site ´ Victor Segalen Bordeaux II, 146 Rue Le ´o-Saignat 33 077 Bordeaux Cedex, France. g.catheline@imf.u-bordeaux2.fr. Individual article reprints may be pur- chased through the Journal Web site, www.anesthesiology.org. Anesthesiology, V 104, No 6, Jun 2006 1257 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/104/6/1257/361843/0000542-200606000-00022.pdf by guest on 01 March 2022