Arrestin-mediated activation of p38 MAPK: molecular mechanisms and behavioral consequences.

Studies of kappa opioid receptor signaling mechanisms during the last decade have demonstrated that agonist activation of the receptor results in Gβγ-dependent signaling and distinct arrestin-dependent signaling events. Gβγ-dependent signaling results in ion channel regulation causing neuronal inhibition, inhibition of transmitter release, and subsequent analgesic responses. In contrast, arrestin-dependent signaling events result in p38 MAPK activation and subsequent dysphoric and proaddictive behavioral responses.

Ligand directed signaling differences between rodent and human κ-opioid receptors.

KOR activation of Gβγ dependent signaling results in analgesia, whereas the dysphoric effects of KOR agonists are mediated by a different pathway involving G protein receptor kinase and non-visual arrestin. Based on this distinction, a partial KOR agonist that does not efficiently activate arrestin-dependent biased signaling may produce analgesia without dysphoria. No KOR-selective partial agonists are currently available, and preclinical assessment is complicated by sequence differences between rodent (r) and human (h) KOR.

Reduction in delayed mortality and subtle improvement in retrograde memory performance in pilocarpine-treated mice with conditional neuronal deletion of cyclooxygenase-2 gene.

Purpose: Pilocarpine induces prolonged status epilepticus (SE) in rodents that results in neurodegeneration and cognitive deficits, both commonly observed to be associated with human temporal lobe epilepsy. The multifunctional neuronal modulator, cyclooxygenase-2 (PTGS2 or COX-2), is rapidly induced after SE, mainly in principal neurons of the hippocampal formation and cortex. We used mice in which COX-2 is conditionally ablated in principal forebrain neurons to investigate the involvement of neuron-derived COX-2 in delayed mortality and performance in the Barnes maze.