THE OPIOID ANALOGUE BUPRENORPHINE ALTERS IN VIVO MYELINATION

EMILSE S. SANCHEZ; SUSAN E. ROBINSON; JOHN W. BIGBEE; CARMEN SATO-BIGBEE

Simposio; Integrative Cellular and Molecular Signaling (ICAMS) Research Retreat; 2007

To avoid "street" drug use and withdrawal symptoms, pregnant opioid addicts are treated with the opioid analoque buprenorphine. Unfortunately, this treatment is associated with increased risk of sudden infant death syndrome as well as child leaming disabilities and behavioral problems. The underlying causes for these conditions are unclear; however, they may in part involve alterations in myelination since oligodendrocytes express opioid receptors in a developmentally requlated manner. To investigate this possibility, pregnant rats were implanted on day 7 of gestation with minipumps to deliver buprenorphine at 0.3-1 rng/kg/day, doses covering the range used in humans. Analysis of their pups at different postnatal ages (12-26 days) indicated that exposure to 0.3 mg/kg/day buprenorphine caused an accelerated and significant increase in the expression of all myelin basic proteins (MBPs) in the brain.ln contrast, treatment with the higher dose caused a developmental delay in MBPs expression. EM analysis of corpus callosum at 26-days of age indicated that buprenorphine cause changes in the´ caliber and number of myelinated axons which is accompanied by a thinner myelin sheath. Analysis of myelin associated glycoprotein (MAG) expression and glycosylation suggests that this molecule may playa crucial role in mediating these buprenorphine effects. Co-immunoprecipitation studies also point to a mechanism involving a MAG-·dependent activation of the tyrosine kinase Pyn. These results show for the nrst time that opioid signaling plays an important role in regulating myelination in vivo and provide cellular and molecular clues that may help to understand the neurological problems affecting children exposed to opioids in utero.