Abstract
Background
Chronic pain and stress-related psychopathologies, such as depression and anxiety-associated
abnormalities, are mutually reinforcing; however, the neuronal circuits and mechanisms
that underlie this reinforcement are still not well understood. Pituitary adenylate
cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate PAC1 receptor (Adcyap1r1) are expressed in peripheral nociceptive pathways, participate in anxiety-related
responses and have been have been linked to posttraumatic stress disorder and other
mental health afflictions.
Methods
Using immunocytochemistry, pharmacological treatments and behavioral testing techniques,
we have used a rodent partial sciatic nerve chronic constriction injury model (n = 5–8 per group per experiment) to evaluate PACAP plasticity and signaling in nociceptive
and stress-related behaviors.
Results
We show that chronic neuropathic pain increases PACAP expression at multiple tiers
along the spinoparabrachioamygdaloid tract. Furthermore, chronic constriction injury
bilaterally augments nociceptive amygdala (in the central nucleus of the amygdala
[CeA]) PACAP immunoreactivity, extracellular signal–regulated kinase phosphorylation,
and c-Fos activation, in parallel with heightened anxiety-like behavior and nociceptive
hypersensitivity. Acute CeA infusions with the PACAP receptor antagonist PACAP(6-38)
blocked chronic constriction injury–induced behavioral responses. Additionally, pretreatments
with inhibitors of mitogen-activated protein kinase enzymes or endocytosis to block
endosomal PACAP receptor extracellular signal–regulated kinase signaling attenuated
PACAP-induced CeA neuronal activation and nociceptive responses.
Conclusions
Our data suggest that chronic pain-induced PACAP neuroplasticity and signaling in
spinoparabrachioamygdaloid projections have an impact on CeA stress- and nociception-associated
maladaptive responses, which can be ameliorated upon receptor antagonism even during
injury progression. Thus, the PACAP pathway provides for an important mechanism underlying
the intersection of stress and chronic pain pathways via the amygdala.
Keywords
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Article Info
Publication History
Published online: August 29, 2016
Accepted:
August 16,
2016
Received in revised form:
July 15,
2016
Received:
February 18,
2016
Identification
Copyright
© Society of Biological Psychiatry, 2016.
