OPIOID ADDICTION AND BRAIN MYELINATION: DIRECT

ESCHENROEDER, AC; SANCHEZ, ES; BIGBEE, JW; ROBINSON, SE; SATO-BIGBEE, C

Congreso; American Society of Neurochemistry; 2010

The increased trend in opioid use represents a critical problem during pregnancy. New substitution therapies in pregnant addicts include the u-opioid receptor agonist and k-opioid receptor antagonist buprenorphine (Bp). While clinical studies demonstrated Bp efficacy in reducing neonatal withdrawal symptoms, there is a lack of information on potential effects on brain development. Interestingly, we recently showed that in utero and postnatal treatment with Bp affects myelination in the developing rat brain. The corpus callosum of pups exposed to Bp exhibited increased caliber myelinated axons with disproportionately thinner myelin sheaths. In addition, exposure to therapeutic Bp levels caused accelerated expression and increased levels of myelin basic proteins (MBPs) while higher doses delayed MBP expression, suggesting effects on oligodendrocyte (OLG) development. In support of this possibility, we found that Bp exerts direct actions on the OLGs which are dependent on both the drug dose and stage of cell differentiation. Exposure of OLG progenitors to Bp results in increased proliferation. However, treatment of more mature pre-OLGs affects morphological differentiation and myelin protein expression. Pre-OLGs exposed to 0.5 uM Bp exhibit extensive cell process networks and membrane outgrowth accompanied by increased expression of MBP splicing isoforms. In contrast, higher Bp concentrations resulted in reduced process formation and MBP levels. These Bp actions were accompanied by changes on activation of ERK1I2 and CREB, signaling molecules that play crucial roles in OLGs. These findings underscore the potential effects of opioid exposure during brain maturation and further indicate a role of opioid signaling in the control of myelination.