title: Reduced serotonin synthesis during early embryogeny changes effect of subsequent prenatal stress on persistent pain in the formalin test in adult male and female rats.
abstract: The considerable evidence supporting a role for serotonin (5-HT) in the embryonic formation of CNS, mediation of prenatal stress, and pain processing is reviewed. Long-term influences of prenatal 5-HT depletion as well as its combination with prenatal stress effects on tonic nociceptive system in 90-day-old Wistar rats were studied in the formalin test. Pregnant dams were injected with para-chlorophenylalanine (pCPA, 400 mg/kg/2 ml, ip), producing 5-HT depletion during the early period of fetal serotonergic system development. The adult offspring from pCPA-treated dams revealed changes in behavioral indices of persistent pain (flexing + shaking and licking) in the formalin test (2.5%, 50 microl) that were accompanied by irreversible morphological alterations in the dorsal raphe nuclei. In the other series of experiments, the role of 5-HT in the mediation of prenatal stress on the behavioral indices of persistent pain was investigated in the adult offspring from dams with 5-HT depletion followed by restraint stress. Stress during the last embryonic week caused much more increase in flexing + shaking and licking in the second tonic phase of the response to formalin in offspring from pCPA- than saline-treated (control) dams. The former was characterized by alterations in the durations of the interphase, the second phase, and the whole behavioral response too. In offspring from pCPA-treated dams, sex dimorphism was revealed in tonic pain evaluated by licking. Together with our previous results in juvenile rats demonstrating the necessity of definite level of prenatal 5-HT for normal development of tonic nociceptive system, the present pioneering findings obtained in adult rats indicate that prenatal 5-HT depletion causes long-term morphological abnormalities in the dorsal raphe nuclei accompanied by alterations in behavioral indices of tonic pain. Early prenatal 5-HT depletion increases vulnerability of tonic nociceptive circuits to the following prenatal stress.
authors.affiliation: Laboratory of Ontogenesis of Nervous System, IP Pavlov Institute of Physiology of the Russian Academy of Sciences, Nab. Makarova, 6. 199034, St. Petersburg, Russia. but@kolt.infran.ru
authors.forename: Irina Pavlovna
authors.initials: IP
authors.lastname: Butkevich
authors.forename: Victor Anatol'evich
authors.initials: VA
authors.lastname: Mikhailenko
authors.forename: Elena Andreevna
authors.initials: EA
authors.lastname: Vershinina
authors.forename: Ludmila Ivanovna
authors.initials: LI
authors.lastname: Khozhai
authors.forename: Igor'Pavlovich
authors.initials: I
authors.lastname: Grigorev
authors.forename: Vladimir Alexandrovich
authors.initials: VA
authors.lastname: Otellin
mesh_terms: D000818:Animals; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D008297:Male; D010146:Pain / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000096:biosynthesis* / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism*
chemical_list: D012701:Serotonin