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Although dynorphins are widely involved in the control of not only nociceptive neurotransmission but also a variety of brain functions such as memory and emotion, no natural regulator for inducing the mRNA expression of prodynorphin (Pdyn), a precursor protein of dynorphins, is known. Using primary cultures of rat cortical neurons, we found that pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon neuropeptide family, markedly induces Pdyn mRNA expression. PACAP was much more effective than VIP, indicating a major role for PAC1 in the PACAP-induced Pdyn mRNA expression. The increase in Pdyn mRNA expression was independent of de novo protein synthesis. Administration of forskolin, an activator for adenylate cyclase/protein kinase A (PKA), but not TPA, an activator for protein kinase C (PKC), induced Pdyn mRNA expression, suggesting a major role for PKA. The involvement of PKA was supported by the inhibition of PACAP-induced Pdyn mRNA expression upon addition of H89, an inhibitor for PKA. The PACAP-induced potentiation of NMDA-R was involved in the mRNA expression of Bdnf or c-fos but not Pdyn. These results suggest PACAP to be an upstream regulator for inducing Pdyn mRNA expression through PKA., (2010 Elsevier Ireland Ltd. All rights reserved.)

Endomorphin 1 (EM1) and endomorphin 2 (EM2) are the endogenous peptides with high affinity and selectivity for the mu-opioid receptor (MOR). We examined whether or not EM1- and EM2-expressing hypothalamic neurons might send their axons to the parabrachial nucleus (PBN), where many MOR-expressing neurons have been observed. Immunofluorescence histochemistry was combined with fluorescent retrograde tract-tracing method. In the rats injected with Fluoro-Gold (FG) into the PBN, some of EM1- and EM2-immunoreactive hypothalamic neurons were labeled retrogradely with FG. The majority of the EM1/FG and EM2/FG double-labeled neurons were distributed in the dorsomedial hypothalamus nucleus, centromedial hypothalamic region, and arcuate nucleus; a few of them were also seen in the periventricular hypothalamic nucleus and posterior hypothalamic nucleus. Endomorphins released from PBN-projecting hypothalamic neurons may modulate the gustatory, autonomic and nociceptive functions through MOR-expressing PBN neurons.

Direct projections from serotonin-, substance P- and tyrosine hydroxylase-like immunoreactive neurons in the midbrain periaqueductal gray (PAG) to the ventromedial hypothalamic nucleus (VMH) in the rat were investigated by the retrograde horseradish peroxidase tracing method combined with the immunocytochemical technique. Serotonin-, substance P- and tyrosine hydroxylase-like immunoreactive PAG neurons sending their axons to the VMH were distributed in the ventrolateral subnucleus and ventral portion of the medial subnucleus of PAG at the middle and caudal levels.