Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes

Abstract

Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain.

Endogenous opioid peptides and brain development: Endomorphin‐1 and Nociceptin play a sex‐specific role in the control of oligodendrocyte maturation and brain myelination

“…Regardless of the downstream mechanisms responsible for EM‐1 and nociceptin interacting effects observed in these studies, particularly intriguing are the present contrasting differences between nociceptin effects in oligodendrocytes and those previously reported by others in developing neurons. Similar to our previous observation (Meyer et al, ) and present findings in cerebral hemispheres of Sprague Dawley rats, a recent peptidomic analysis in Wistar rats identified the presence of elevated levels of nociceptin during cerebellar development, with concentrations significantly declining beyond PD 8 (Corbiere et al, ). Interestingly, the finding of supportive nociceptin actions on rat cerebellar granule neurons (Corbiere et al, ) together with earlier observations of positive effects on neurite outgrowth in mouse hippocampal cells (Ring et al, ) are indicative of an important stimulatory role of nociceptin on neuronal development.…”

“…Our previous analysis of nociceptin levels in the developing rat brain utilized combined pools that did not discriminate values by sex (Meyer et al, ). However, similar to those earlier findings, Figure 1a now shows that in both the male and female brain, nociceptin exhibits the highest expression levels between 2 and 5 days of age.…”

“…Prior to the analysis of myelin proteins, the tissue was homogenized in PBS containing a protease and phosphatase inhibitor cocktail. For processing of tissue for immunohistochemical analyses, the 14‐day‐old pups were anesthetized with 2.5% Avertin and then perfused transcardially with 4% paraformaldehyde (PFA) as previously described (Meyer et al, ). Brains were removed, post‐fixed in 4% PFA, and cryopreserved overnight in 30% sucrose prior to flash freezing in OCT.…”

“…Initial studies implicated NOR in pain modulatory functions, that depending on the site of nociceptin administration, could result in either hyperalgesia or analgesia (Heinricher, McGaraughty, & Grandy, ; Pan, Hirakawa, & Fields, ; Rizzi et al, ). Nevertheless, findings from different laboratories indicated that the nociceptin system is also involved in a wide variety of actions, including effects on learning and memory (Noda et al, ), stress (Jenck et al, ; Koster et al, ), drug addiction (Chung, Pohl, Zeng, Civelli, & Reinscheid, ; Lutfy, Do, & Maidment, ; Lutfy & Zaveri, ; Marquez, Borse, Nguyen, Hamid, & Lutfy, ; Marquez, Nguyen, Hamid, & Lutfy, ; Zaveri, Marquez, Meyer, Hamid, & Lutfy, ), and the control of glutamate transporter levels and activity in developing rodent and human astrocytes (Meyer et al, ). As indicated above, our previous studies suggested that MOR and NOR mediated methadone and buprenorphine effects on myelination.…”

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

“…NOP receptor mRNA was found in microglia and astrocytes in adult rat brain (119) or in astrocytes in rat brain until the third postnatal week, and in fetal human brain (120) by in situ hybridization for NOP receptor mRNA combined with immunofluorescent staining of microglia and astrocyte markers. Proteins of DOP, KOP, and NOP receptors were detected in astrocytes or oligodendrocytes in mouse or rat brain, but the staining specificity of antibodies was not unequivocally proven or not tested (108,120).…”