Abstract
Serotonin (5-HT) contributes to the prenatal development of the central nervous system, acting as a morphogen in the young embryo and later as a neurotransmitter. This biologically active agent influences both morphological and biochemical differentiation of raphe neurons, which give rise to the descending serotonergic paths that regulate the processing of acutely evoked nociceptive inputs. The involvement of 5-HT in the prenatal development of tonic nociceptive system has not been studied. In the present study we evaluated the effects of a single injection (400 mg/kg, 2 ml, i.p.) of the 5-HT synthesis inhibitor, para-chlorophenylalanine (pCPA), given to pregnant rats during the critical period fetal serotonin development. The functional integrity of the tonic nociceptive response was investigated in 25 day old rats using the classic formalin test. Morphological analysis of brain structures involved in formalin-induced pain and 5-HT levels in the heads of 12-day embryos were also evaluated. Embryonic levels of 5-HT were significantly lowered by the treatment. The juvenile rats from pCPA-treated females showed altered brain morphology and cell differentiation in the developing cortex, hippocampus, raphe nuclei, and substantia nigra. In the formalin test, there were significant decreases in the intensity and duration of the second phase of the formalin-induced response, characterizing persistent, tonic pain. The extent of impairments in the brain structures correlated positively with the level of decrease in the behavioral responses. The data demonstrate the involvement of 5-HT in the prenatal development of the tonic nociceptive system. The decreased tonic component of the behavioral response can be explained by lower activity of the descending excitatory serotonergic system originating in the raphe nuclei, resulting in decreased tonic pain processing organized at the level of the dorsal horn of the spinal cord.
Highlights
Serotonin (5-HT) plays an important role in regulating the development of the central nervous system [1,2,3,4]
We focused our attention on investigation of the tonic component of nociceptive system in the juvenile (25-day-olds) offspring of rats born to females, who during a critical period of development of fetal serotonergic development were treated with an inhibitor of 5-HT synthesis, para-chlorophenylalanine
The treatment of rats with pCPA on day 9 of pregnancy led to significant changes in formalin-induced pain in their 25-day-old offspring and severe morphological alterations in brain structures involved in formalin-induced pain, compared to offspring from control females
Summary
Serotonin (5-HT) plays an important role in regulating the development of the central nervous system [1,2,3,4]. Deficiency of 5-HT in early embryogenesis, when this biologically active substance influences cell and tissue development, causes disorders in neurogenesis [5,6] and abnormalities of development of brain and its transmitter systems. Consequences of these abnormalities persist into (page number not for citation purposes). To understand the role of 5-HT in the development of pain processing, we decreased 5-HT content in fetal brain during the period when there is active development of nociceptive systems. The formalin test, unlike other tests that are usually used for nociception estimation, favors studies of the feedback-type modulation effects and endogenous systems of pain regulation, including the descending serotonergic system
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