title: Naturally occurring variations in maternal care modulate the effects of repeated neonatal pain on behavioral sensitivity to thermal pain in the adult offspring.
abstract: Repeated pain during a critical period of development can have long-term behavioral and physiological consequences in both human and animals. We previously showed that rat mothers caring for pups subjected to mild pain in neonatal life increased pup licking and grooming behavior. Therefore, we tested whether naturally occurring variations in maternal behavior would modulate the effects of repeated mild inflammatory pain on behavioral responses to pain and stress in the adult male offspring. Rat pups were either uninjected (UI) or injected twice daily between PND3 and PND14 with either saline (0.9%) or formalin (0.2-0.4%) in the footpad of the hindpaw. Maternal behavior (pup licking and grooming) was recorded under basal conditions and after reunion with the litter post injection to determine maternal phenotype (High, Middle, Low licking). Adult offspring (PND60) were tested for their thermal sensitivity, inflammatory pain responses after formalin injection and neuroendocrine responses to formalin injection. Maternal phenotype significantly altered pain sensitivity after thermal stimulation, but not formalin injection. Offspring from the High licking mothers displayed increased withdrawal latencies compared to offspring from Low mothers, regardless of neonatal treatment. Pain responses after formalin injection were higher in offspring receiving formalin as neonates compared to saline-treated or uninjected rats, demonstrating a long lasting increased sensitivity to inflammatory pain. Neuroendocrine responses to pain stress were not affected by neonatal treatment. These data suggest that changes in maternal behavior can influence some modalities of pain sensitivity and that repeated mild inflammatory pain in neonatal period causes hypersensitivity to formalin in the adult offspring.
authors.affiliation: Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada School of Nursing, McGill University, Montreal, Canada.
authors.forename: Claire-Dominique
authors.initials: CD
authors.lastname: Walker
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Xu
authors.forename: Joseph
authors.initials: J
authors.lastname: Rochford
authors.forename: Celeste C
authors.initials: CC
authors.lastname: Johnston
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D005260:Female; D008425:Maternal Behavior; D009035:Mothers; D010146:Pain / Q000503:physiopathology*; D017288:Pain Threshold; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
references.citation: Abbott FV, Ocvirk R, Najafee R, Franklin KB. Improving the efficiency of the formalin test. Pain. 1999;83:561-569.
references.citation: Abbott FV, Franklin KB, Westbrook RF. The formalin test: scoring properties of the first and second phases of the pain response in rats. Pain. 1995;60:91-102.
references.citation: Alvares D, Torsney C, Beland B, Reynolds M, Fitzgerald M. Modelling the prolonged effects of neonatal pain. Prog Brain Res. 2000;129:365-373.
references.citation: Anand KJ, Garg S, Rovnaghi CR, Narsinghani U, Bhutta AT, Hall RW. Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res. 2007;62:283-290.
references.citation: Anand KJ, Scalzo FM. Can adverse neonatal experiences alter brain development and subsequent behavior? Biol Neonate. 2000;77:69-82.
references.citation: Anand KJS, Coskun V, Thrivikraman KV, Nemeroff CV, Plotsky PM. Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav. 1999;66:627-637.
references.citation: Anseloni VC, He F, Novikova SI, Turnbach Robbins M, Lidow IA, Ennis M, et al. Alterations in stress-associated behaviors and neurochemical markers in adult rats after neonatal short-lasting local inflammatory insult. Neuroscience. 2005;131:635-645.
references.citation: Bhutta AT, Rovnaghi C, Simpson PM, Gossett JM, Scalzo FM, Anand KJ. Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects. Physiol Behav. 2001;73:51-58.
references.citation: Bilgen H, Ozek E, Cebeci D, Ors R. Comparison of sucrose, expressed breast milk, and breast-feeding on the neonatal response to heel prick. J Pain. 2001;2:301-305.
references.citation: Blass EM, Shide DJ, Zaw-Mon C, Sorrentino J. Mother as shield: differential effects of contact and nursing on pain responsivity in infant rats – evidence for nonopioid mediation. Behav Neurosci. 1995;109:342-353.
references.citation: Blom JM, Benatti C, Alboni S, Capone G, Ferraguti C, Brunello N, et al. Early postnatal chronic inflammation produces long-term changes in pain behavior and N-methyl-d-aspartate receptor subtype gene expression in the central nervous system of adult mice. J Neurosci Res. 2006;84:1789-1798.
references.citation: Breton JD, Veinante P, Uhl-Bronner S, Vergnano AM, Freund-Mercier MJ, Schlichter R, et al. Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify gabaergic inhibition. Mol Pain. 2008;4:19.
references.citation: Champagne FA, Francis DD, Mar A, Meaney MJ. Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol Behav. 2003;79:359-371.
references.citation: Chatterjee D, Chatterjee-Chakraborty M, Rees S, Cauchi J, de Medeiros CB, Fleming AS. Maternal isolation alters the expression of neural proteins during development: ‘Stroking’ stimulation reverses these effects. Brain Res. 2007;1158:11-27.
references.citation: Chung EK, Zhang X, Li Z, Zhang H, Xu H, Bian Z. Neonatal maternal separation enhances central sensitivity to noxious colorectal distention in rat. Brain Res. 2007;1153:68-77.
references.citation: Clancy B, Kersh B, Hyde J, Darlington RB, Anand KJ, Finlay BL. Web-based method for translating neurodevelopment from laboratory species to humans. Neuroinformatics. 2007;5:79-94.
references.citation: Condés-Lara M, Rojas-Piloni G, Martínez-Lorenzana G, Rodríguez-Jiménez J, López Hidalgo M, Freund-Mercier MJ. Paraventricular hypothalamic influences on spinal nociceptive processing. Brain Res. 2006;1081:126-137.
references.citation: Efe E OZ. The use of breast-feeding for pain relief during neonatal immunization injections. Appl Nursing Res ANR. 2007;10-16.
references.citation: Fitzgerald M, Millard C, mcintosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia. Pain. 1989;39:31-36.
references.citation: Gray L, Watt L, Blass EM. Skin-to-skin contact is analgesic in healthy newborns. Pediatrics. 2000;105:e14.
references.citation: Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:77-88.
references.citation: Hermann C, Hohmeister J, Demirakca S, Zohsel K, Flor H. Long-term alteration of pain sensitivity in school-aged children with early pain experiences. Pain. 2006;125:278-285.
references.citation: Hohmann AG, Neely MH, Piña J, Nackley AG. Neonatal chronic hind paw inflammation alters sensitization to intradermal capsaicin in adult rats: a behavioral and immunocytochemical study. J Pain. 2005;6:798-808.
references.citation: Hunskaar S, Hole K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain. 1987;30:103-114.
references.citation: Johnston CC, Filion F, Campbell-Yeo M, Goulet C, Bell L, Finley GA, et al. Kangaroo mothercare diminishes pain from heel lance in very preterm neonates: a crossover trial. BMC Pediatrics. 2008;8:13.
references.citation: Johnston CC, Filion F, Nuyt AM. Recorded maternal voice for preterm neonates undergoing heel lance. Adv Neonatal Care. 2007;7:258-266.
references.citation: Johnston CC, Stevens B, Pinelli J, Gibbins S, Filion F, Jack A, et al. Kangaroo care is effective in diminishing pain response in preterm neonates. Arch Pediat Adolesc Med. 2003;157:1084-1088.
references.citation: Johnston CC, Walker CD. The effects of exposure to repeated minor pain during the neonatal period on formalin pain behaviour and thermal withdrawal latencies. Pain Res Manag. 2003;8:213-217.
references.citation: Johnston CC, Walker CD, Boyer K. Animal models of long-term consequences of early exposure to repetitive pain. Clin Perinatol. 2002;29:395-414.
references.citation: Johnston CC, Stremler RL, Stevens BJ, Horton LJ. Effectiveness of oral sucrose and simulated rocking on pain response in preterm neonates. Pain. 1997;72:193-199.
references.citation: Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response. Pediatrics. 1996;98:925-930.
references.citation: Kaffman A, Meaney MJ. Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. J Child Psychol Psychiatry. 2007;48:224-244.
references.citation: Kalinichev M, Easterling KW, Holtzman SG. Repeated neonatal maternal separation alters morphine-induced antinociception in male rats. Brain Res Bull. 2001;54:649-654.
references.citation: Komisaruk BR, Sansone G. Neural pathways mediating vaginal function: the vagus nerves and spinal cord oxytocin. Scand J Psychol. 2003;44:241-250.
references.citation: Léonhardt M, Matthews SG, Meaney MJ, Walker CD. Psychological stressors as a model of maternal adversity: diurnal modulation of corticosterone responses and changes in maternal behavior. Horm Behav. 2007;51:77-88.
references.citation: Lidow MS. Long-term effects of neonatal pain on nociceptive systems. Pain. 2002;99:377-383.
references.citation: Lidow MS, Song ZM, Ren K. Long-term effects of short-lasting early local inflammatory insult. Neuroreport. 2001;12:399-403.
references.citation: Lippmann M, Bress A, Nemeroff CB, Plotsky PM, Monteggia LM. Long-term behavioural and molecular alterations associated with maternal separation in rats. Eur J Neurosci. 2007;25:3091-3098.
references.citation: Ludington-Hoe SM, Hosseini R, Torowizc DL. Skin-to-skin contact (Kangaroo Care) analgesia for preterm infant heelstick. AACN Clin Issues. 2005;16:373-387.
references.citation: Meaney MJ, Szyf M. Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci. 2005;7:103-123.
references.citation: Meaney MJ, Diorio J, Francis D, Weaver S, Yau J, Chapman K, et al. Postnatal handling increases the expression of camp-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin. J Neurosci. 2000;20:3926-3935.
references.citation: Ors R, Ozek E, Baysoy G, Cebeci D, Bilgen H, Turkuner M, et al. Comparison of sucrose and human milk on pain response in newborns. Eur J Pediat. 1999;158:63-66.
references.citation: Phillips RM, Chantry CJ, Gallagher MP. Analgesic effects of breast-feeding or pacifier use with maternal holding in term infants. Ambulatory Pediat. 2005;5:359-364.
references.citation: Rojas-Piloni G, López-Hidalgo M, Martínez-Lorenzana G, Rodríguez-Jiménez J, Condés-Lara M. GABA-mediated oxytocinergic inhibition in dorsal horn neurons by hypothalamic paraventricular nucleus stimulation. Brain Res. 2007;1137:69-77.
references.citation: Ruda MA, Ling Q-D, Hohmann AG, Peng BP, Tachibana T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science. 2000;289:628-631.
references.citation: Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediat Adoles Med. 2003;157:1058-1064.
references.citation: Stephan M, Helfritz F, Pabst R, von Hörsten S. Postnatally induced differences in adult pain sensitivity depend on genetics, gender and specific experiences: reversal of maternal deprivation effects by additional postnatal tactile stimulation or chronic imipramine treatment. Behav Brain Res. 2002;133:149-158.
references.citation: Stevens B, mcgrath P, Gibbins S, Beyene J, Breau L, Camfield C, et al. Procedural pain in newborns at risk for neurologic impairment. Pain. 2003;105:27-35.
references.citation: Taddio A, Katz J. The effects of early pain experience in neonates on pain responses in infancy and childhood. Paediat Drugs. 2005;7:245-257.
references.citation: Teng CJ, Abbott FV. The formalin test: a dose-response analysis at three developmental stages. Pain. 1998;76:337.
references.citation: Ueyama T, Arakawa H, Mizuno N. Central distribution of efferent and afferent components of the pudendal nerve in rat. Anat Embryol (Berl). 1987;177:37-49.
references.citation: Uvnäs-Moberg K, Bruzelius G, Alster P, Lundeberg T. The antinociceptive effect of non-noxious sensory stimulation is mediated partly through oxytocinergic mechanisms. Acta Physiol Scand. 1993;149:199-204.
references.citation: Walker CD, Johnston CC, Kudreikis K. Sherrard A: repeated neonatal pain influences maternal behavior, but not stress responsiveness in rat offspring. Dev Brain Res. 2003;140:253-261.
references.citation: Weaver SA, Diorio J, Meaney MJ. Maternal separation leads to persistent reductions in pain sensitivity in female rats. J Pain. 2007;8:962-969.
references.citation: Yanagimoto M, Honda K, Goto Y, Negoro H. Afferents originating from the dorsal penile nerve excite oxytocin cells in the hypothalamic paraventricular nucleus of the rat. Brain Res. 1996;733:292-296.