Regulation of Spinal Dynorphin 1-17 Release by Endogenous Pituitary Adenylyl Cyclase-Activating Polypeptide in the Male Rat: Relevance of Excitation via Disinhibition

Abstract

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 PAC 1 (PAC 1 R) inhibited, whereas PAC 1 R blockade augmented, spinal release of Dyn. It is noteworthy that in the formalin-induced pain model PAC 1 R blockade (via PACAP6-38) also resulted in antinociception that was abolished by spinal -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 PAC 1 R 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.

Pleiotropic Opioid Regulation of Spinal Endomorphin 2 Release and Its Adaptations to Opioid Withdrawal Are Sexually Dimorphic

“…A permanent indwelling cannula was inserted into the lumbar spinal cord subarachnoid space as used previously (Liu et al, 2011). In brief, in anesthetized animals, a saline-filled catheter (PE-10; Clay Adams, Parsippany, NJ) was introduced through a small incision in the atlanto-occipital membrane, slowly inserted into the subarachnoid space, and secured in place.…”

Sex, Pain, and Opioids: Interdependent Influences of Sex and Pain Modality on Dynorphin-Mediated Antinociception in Rats

“…The intrathecal space was perfused (5 ml/minute) using the push-pull method as previously implemented (Liu et al, 2011b). Two PE-10 catheters (8.5 cm length for inflow and 7.0 cm for outflow) were introduced into the spinal subarachnoid space via the atlanto-occipital membrane under sodium pentobarbital anesthesia (40 and 50 mg/kg i.p.…”

“…The content of Dyn in intrathecal perfusate was quantified using a competitive enzyme immunoassay performed as instructed by the manufacturer (Peninsula Laboratories Inc., San Carlos, CA) and as previously used (Liu et al, 2011b). The anti-Dyn antibody used for immunoassay of perfusate is highly selective for Dyn: it does not recognize dynorphin 1-13, dynorphin 1-8, a-Neoendorphin, b-endorphin, dynorphin B, or Leu-enkephalin (see Gintzler et al, 2008, for further characterization).…”

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

“…PACAP also modulates inflammatory, neuropathic, and visceral pain-like behaviors based on results in experimental models (Bon et al, 1998;Ohsawa et al, 2002;Shimizu et al, 2004). Evidence suggests that the modulation of nociception by PACAP involves activation of PAC 1 , since most of the behaviors could be inhibited by a selective antagonist, PACAP 6-38 , through an interaction with dynorphin release within the spinal cord (Davis-Taber et al, 2008;Liu et al, 2011). Thus, PAC 1 regulates not only the stress response but also some pain-like behaviors, making it a prime target to treat stress-associated chronic pain.…”