δ‐opioid receptor activation leads to neurite outgrowth and neuronal differentiation via a STAT 5B‐Gαi/o pathway

It remains unclear how opioid receptors (δ, μ, κ) are implicated in mechanisms controlling differentiation, cell proliferation, and survival. Opioid receptors are coupled to Gi/Go proteins and recent findings have shown that opioid receptors can form a multicomponent signaling complex, consisting of members of G protein and the signal transducer and activator of transcription ( STAT )5B. We thus wondered whether activation of the opioid receptors could direct differentiation and neurite outgrowth through a molecular pathway involving STAT 5B and other signaling intermediates. We demonstrate that prolonged δ‐opioid receptor (δ‐OR) activation with opioid agonists induces STAT 5B phosphorylation in Neuro‐2A cells. Moreover, [D‐Ser2, Leu5, Thr6]‐enkephalin‐activation of δ‐OR triggers neurite outgrowth and neuronal survival; these effects are blocked by the selective antagonist naltrindole, by treatment with pertussis toxin, and after expression of a dominant negative mutant of STAT 5B ( DN ‐ STAT 5B), suggesting that the signaling pathway participating in this mechanism involves Gi/o proteins and p‐ STAT 5B. Additional studies have shown that while [D‐Ser 2 , Leu 5 , Thr 6 ]‐enkephalin exposure of neuroblastoma cells induces a marked increase in the differentiation marker proteins, β III ‐tubulin (Tuj‐1), synaptophysin, and neural cell adhesion molecule, over‐expression of the DN ‐ STAT 5B attenuated significantly their expression levels. Taken together, our findings demonstrate that δ‐ OR activation leads to a number of neurotropic events via a Gαi/o‐linked and STAT 5B‐dependent manner.We propose a novel signalling pathway for δ‐opioid receptor (δ‐ΟR)‐mediated neurotropic events. STAT5B interacts with the δ‐ΟR and upon prolonged receptor activation phosphorylates STAT5B in a Gi/Go dependent manner leading to increased neuronal survival, neurite outgrowth and differentiation. These findings contribute to a better understanding of the molecular and cellular events following δ‐OR activation and suggest a possible neuroprotective role opioids could exert.