The Effect of Opiates on the Developing Cerebral Cortex

Opiate drugs, such as codeine, morphine and heroin are powerful analgesics and drugs of abuse. The unborn child is invariably exposed to opiate drugs as a consequence of maternal use. Studies that have investigated the impact of opiate drugs demonstrated opioid system expression in proliferating regions of the developing brain, as well as on proliferative astroglia taken from the developing central nervous system. The effects of opiates on astroglial proliferation (largely mediated by the mu opioid receptor) are predominantly inhibitory, but are extremely context dependent. This context dependency exists because of the complexity resident within the opioid signalling system. However, since this previous research was conducted, there has been impressive progress made in the field of developmental neurobiology with the demonstration that cells of astrocytic lineage are responsible for the generation of the central nervous system. It was therefore the aim of the current research project to investigate the developmental impact of opiate exposure in the context of the foetal mouse cerebral cortex. This aim was divided into 3 separate aims that comprised of; determining the cellular localisation of the mu opioid receptor, the effects of opiate exposure on cortical progenitor cells, and to determine the effect of opiate exposure on the development of the cerebral cortex itself. The mu opioid receptor was expressed on proliferative radial glia of both the embryonic day 15.5 (neurogenic) and embryonic day 18.5 (gliogenic) ventricular zone of the dorsal forebrain. Interestingly and significantly, the mu opioid receptor-positive glia observed in the embryonic day 18.5 mouse forebrain were also observed at a comparable developmental stage in the foetal human forebrain. Morphine exposure slowed down G2 phase of the cell cycle at embryonic day 15.5 in the neurogenic murine cortical ventricular zone. This opiate-induced slowing in cell cycle progression was shown not to impact on proliferation in the ventricular zone, although future research should address whether this perturbation altered differentiation or developmental maturation of the radial glia. Morphine exposure throughout corticogenesis decreased levels of doublecortin expression (a migratory neuronal marker) at the end of gestation. Postnatally, mice exposed to morphine during corticogenesis also showed decreased numbers of neurons in layer V of the cerebral cortex. Collectively, this thesis presents the first evidence that shows morphine affects cortical progenitor cells in vivo. This research supports the possibility that the opioid system plays an endogenous role in corticogenesis. The clinical significance is morphine has the potential to perturb normal development of the cerebral cortex.