Summary: New research clarifies a long-observed link between chronic pain and anxiety and identifies a molecular pathway that could be targeted for treatment.
Source: University of Vermont.
Researchers have identified a specific stress-related peptide that rises in response to neuropathic pain and appears to drive both pain sensitivity and anxiety-like behaviors, suggesting a promising therapeutic target. The findings, published in Biological Psychiatry, show that increased expression of PACAP — pituitary adenylate cyclase-activating polypeptide — along a spinal-to-amygdala pathway contributes to the emotional component of chronic pain.
The team focused on PACAP signaling along the spino-parabrachioamygdaloid tract, a pathway that carries nociceptive information from the spinal cord to the amygdala, the brain region central to emotion and fear. Using well-established rodent models of chronic neuropathic pain and anxiety-like behaviors, along with techniques to trace PACAP-containing neural circuits, the researchers mapped where stress and pain pathways overlap and how they interact.
Senior author Victor May, Ph.D., professor of neurological sciences at the University of Vermont, notes that chronic pain and anxiety disorders commonly occur together. Earlier work from his group linked PACAP to stress-related disorders such as PTSD, and the current study extends that connection to chronic pain.
In their experiments, the researchers observed that chronic constriction injury (a model of neuropathic pain) increases PACAP expression at multiple levels of the spino-parabrachioamygdaloid pathway. This upregulation coincided with increased markers of neuronal activation in the central amygdala, heightened ERK phosphorylation (a signaling event often linked with plasticity), and elevated anxiety-like and pain-related behaviors.
Importantly, blocking PACAP signaling in the amygdala reduced both anxiety-like responses and pain hypersensitivity. Infusion of a PACAP receptor antagonist into the central amygdala prevented the behavioral consequences of chronic neuropathic injury. Additional experiments showed that interfering with MEK (a kinase upstream of ERK) or inhibiting receptor endocytosis, which disrupts endosomal PACAP receptor signaling, also diminished PACAP-driven neuronal activation and reduced nociceptive behaviors.
“By targeting PACAP signaling in this pathway, we have an opportunity to reduce both chronic pain and associated anxiety,” says May. He and colleagues plan to collaborate with chemists to develop small-molecule antagonists that can block PACAP actions, offering an alternative to current treatments such as benzodiazepines or opioids.
The study was carried out using immunocytochemistry, pharmacological manipulations, behavioral testing, and a rodent partial sciatic nerve chronic constriction model to evaluate PACAP-driven plasticity and signaling in circuits that link nociception and stress-related behavior. Results demonstrate that chronic neuropathic pain increases PACAP signaling along spinal, parabrachial, and amygdala projections, which in turn modulate emotional and nociceptive responses.
Blocking PACAP receptors in the central amygdala, or disrupting downstream ERK signaling, was sufficient to attenuate both neuronal activation and behavioral symptoms even while injury persisted. These findings indicate that PACAP-driven plasticity in the spino-parabrachioamygdaloid pathway is a mechanistic link between chronic pain and anxiety-like disorders and that receptor antagonism may be an effective way to alleviate the maladaptive emotional component of chronic pain.
Authors and contributors: The research team includes Galen Missig, Ph.D.; Linda Mei; Margaret Vizzard, Ph.D.; Karen Braas, Ph.D.; James Waschek, Ph.D.; Kerry Ressler, M.D., Ph.D.; Sayamwong Hammack, Ph.D.; and Victor May, Ph.D., with affiliations to the University of Vermont and collaborating institutions.
Funding: Supported by the National Institutes of Health and the National Center for Research Resources.
Background: Chronic pain and stress-related psychiatric conditions such as anxiety and depression commonly reinforce one another, yet the neural circuits that mediate this interaction are not fully understood. PACAP and its PAC1 receptor are implicated in nociceptive processing and stress responses.
Methods: Using a rodent chronic constriction injury model, combined with anatomical, pharmacological, and behavioral approaches, the study examined PACAP expression and signaling along the spino-parabrachioamygdaloid tract and assessed consequences for amygdala activation and behavior.
Results: Chronic neuropathic pain increases PACAP expression across the pathway and elevates central amygdala ERK phosphorylation and neuronal activation, together with anxiety-like behavior and heightened nociception. Local PACAP receptor antagonism or blockade of endosomal ERK signaling reduced these effects.
Conclusions: Chronic pain induces PACAP-dependent neuroplasticity within spino-parabrachioamygdaloid projections, driving maladaptive emotional and nociceptive responses via the amygdala. Targeting PACAP signaling presents a promising approach to treat the overlapping symptoms of chronic pain and anxiety.
Original research: “Parabrachial PACAP Activation of Amygdala Endosomal ERK Signaling Regulates the Emotional Component of Pain,” Biological Psychiatry, published online August 29, 2016. DOI: 10.1016/j.biopsych.2016.08.025