PT  - JOURNAL ARTICLE
AU  - Nai-Jiang Liu
AU  - Stephen A. Schnell
AU  - Stefan Schulz
AU  - Martin W. Wessendorf
AU  - Alan R. Gintzler
TI  - Regulation of Spinal Dynorphin 1-17 Release by Endogenous Pituitary Adenylyl Cyclase-Activating Polypeptide in the Male Rat: Relevance of Excitation via Disinhibition
AID  - 10.1124/jpet.110.173039
DP  - 2011 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 328--335
VI  - 336
IP  - 2
4099  - http://jpet.aspetjournals.org/content/336/2/328.short
4100  - http://jpet.aspetjournals.org/content/336/2/328.full
SO  - J Pharmacol Exp Ther2011 Feb 01; 336
AB  - Opioids inhibit release of primary afferent transmitters but it is unclear whether the converse occurs. To test the hypothesis that primary afferent transmitters influence opioid-ergic tone, we studied the functional and anatomical relationships between pituitary adenylyl cyclase-activating polypeptide (PACAP) and dynorphin 1-17 (Dyn) in spinal cord. We found that activation of the PACAP-specific receptor PAC1 (PAC1R) inhibited, whereas PAC1R blockade augmented, spinal release of Dyn. It is noteworthy that in the formalin-induced pain model PAC1R blockade (via PACAP6-38) also resulted in antinociception that was abolished by spinal κ-opioid receptor blockade. These findings indicate that Dyn release is tonically inhibited by PACAP and that blocking this inhibition, which increases the spinal release of Dyn, results in antinociception. Consistent with this conclusion, we found in the spinal dorsal horn that Dyn-immunoreactive neurons 1) expressed PAC1R and 2) were apposed by PACAP terminals. Present results, in combination with the previous demonstration that the release of spinal Dyn is tonically inhibited by opioid- and nociceptin/orphanin FQ-coupled pathways (J Pharmacol Exp Ther 298:1213–1220, 2001), indicate that spinal Dyn-ergic neurons integrate multiple inhibitory inputs, the interruption of any one of which (i.e., disinhibition) is sufficient to enhance spinal Dyn release and generate antinociception. Gaining a better understanding of the role of primary afferent neurotransmitters in negatively modulating the spinal release of Dyn and the physiological use of disinhibition to increase spinal Dyn activity could suggest novel clinically useful approaches for harnessing endogenous Dyn for pain control.