Summary: Researchers provide new insight into the little understood connection between chronic pain and anxiety.
Source: University of Vermont.
New research provides insight into a long-observed, but little-understood connection between chronic pain and anxiety and offers a potential target for treatment. The study’s findings, published as an Article in Press in Biological Psychiatry, show that increased expression of PACAP – a peptide neurotransmitter the body releases in response to stress – is also increased in response to neuropathic pain and contributes to these symptoms.
The researchers examined the expression of PACAP (pituitary adenylate cyclase activating polypeptide) along one of the nervous system’s pathways to the brain – the spino-parabrachiomygdaloid tract – which travels from the spinal cord to the amygdala, the brain’s home base for emotional behavior.
Using models for chronic pain and anxiety, as well as models that can trace PACAP neurocircuits, the team members were able to observe where the stress and chronic pain pathways intersected.
“Chronic pain and anxiety-related disorders frequently go hand-in-hand,” says senior author Victor May, Ph.D., professor of neurological sciences at the University of Vermont (UVM). In a 2011 study, he and members of the research team found that PACAP was highly expressed in women exhibiting PTSD symptoms.
While May and his colleagues saw an increase in anxiety-related behaviors in models of chronic pain, the anxious behavior and pain hypersensitivity were significantly reduced when a PACAP receptor antagonist – designed to block the response – was applied.
“By targeting this regulator and pathway, we have opportunities to block both chronic pain and anxiety disorders,” says May, whose next step is to work with University of Vermont chemistry colleagues to develop small molecule compounds that can antagonize PACAP actions.
“This would be a completely different approach to using benzodiazepine and opioids – it’s another tool in the arsenal to battle chronic pain and stress-related behavioral disorders.”
May’s coauthors on the study include Galen Missig, Ph.D., former UVM neuroscience graduate student; Linda Mei, UVM research technician; Margaret Vizzard, Ph.D., UVM professor of neurological sciences; Karen Braas, Ph.D., UVM associate professor of neurological sciences; James Waschek, Ph.D., professor of psychiatry and behavioral sciences, David Geffen School of Medicine, University of California Los Angeles; Kerry Ressler, M.D., Ph.D., chief, Division of Depression and Anxiety, McLean Hospital – Harvard Medical School; and Sayamwong Hammack, Ph.D., UVM associate professor of psychological science.
Funding: Funding provided by National Institutes of Health, National Center for Research Resources.
Source: Jennifer Nachbur – University of Vermont
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Parabrachial PACAP Activation of Amygdala Endosomal ERK Signaling Regulates the Emotional Component of Pain” by Galen Missig, Linda Mei, Margaret A. Vizzard, Karen M. Braas, James A. Waschek, Kerry J. Ressler, Sayamwong E. Hammack, and Victor May in Biological Psychiatry. Published online August 29 2016 doi:10.1016/j.biopsych.2016.08.025
[cbtabs][cbtab title=”MLA”]University of Vermont. “Connection Between Chronic Pain and Anxiety Disorders.” NeuroscienceNews. NeuroscienceNews, 1 September 2016.
<https://neurosciencenews.com/chronic-pain-anxiety-4951/>.[/cbtab][cbtab title=”APA”]University of Vermont. (2016, September 1). Connection Between Chronic Pain and Anxiety Disorders. NeuroscienceNew. Retrieved September 1, 2016 from https://neurosciencenews.com/chronic-pain-anxiety-4951/[/cbtab][cbtab title=”Chicago”]University of Vermont. “Connection Between Chronic Pain and Anxiety Disorders.” https://neurosciencenews.com/chronic-pain-anxiety-4951/ (accessed September 1, 2016).[/cbtab][/cbtabs]
Parabrachial PACAP Activation of Amygdala Endosomal ERK Signaling Regulates the Emotional Component of Pain
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 (PTSD) and other mental health afflictions.
Using immunocytochemistry, pharmacological treatments and behavioral testing techniques, we have used a rodent partial sciatic nerve chronic constriction model (CCI; n = 5 – 8 per group per experiment) to evaluate PACAP plasticity and signaling in nociceptive and stress-related behaviors.
We show that chronic neuropathic pain increases PACAP expression at multiple tiers along the spino-parabrachioamygdaloid tract. Furthermore, CCI bilaterally augments nociceptive amygdala (CeA) PACAP immunoreactivity, ERK 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 CCI-induced behavioral responses. Additionally, pretreatments with inhibitors of MEK or endocytosis to block endosomal PACAP receptor ERK signaling attenuated PACAP-induced CeA neuronal activation and nociceptive responses.
Our data suggest that chronic pain-induced PACAP neuroplasticity and signaling in spino-parabrachioamygdaloid projections impact 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.
“Parabrachial PACAP Activation of Amygdala Endosomal ERK Signaling Regulates the Emotional Component of Pain” by Galen Missig, Linda Mei, Margaret A. Vizzard, Karen M. Braas, James A. Waschek, Kerry J. Ressler, Sayamwong E. Hammack, and Victor May in Biological Psychiatry. Published online August 29 2016 doi:10.1016/j.biopsych.2016.08.025