PACAP Circuits Mediating the Sensory and Behavioral Consequences of Pain

The co-prevalence of stress-related psychopathologies with chronic pain has implicated common mechanistic underpinnings. PACAP has been associated with chronic stress-related behaviors and disorders; the expression and regulation of PACAP and PAC1 receptors in sensory pathways have implicated the PACAPergic system in nociceptive signaling. Although conflicting effects of PACAP in mediating anti-nociception or pro-nociception have been reported in peripheral vs. central peptide infusion experiments, neuropathic and inflammatory pain studies using PACAP or PAC1 receptor knockout mice have consistently illustrated the pro-nociceptive action of PACAP signaling. PACAP has recently been identified in the parabrachioamygdaloid tract which transmits nociceptive information from the dorsal horn of the spinal cord to the pontine lateral parabrachial nucleus (LPBn), where PACAP neurons project to the lateral capsular division of the central amygdala (CeLC), or the nociceptive amygdala. The amygdala is the principal integration center for emotional responses; hence these observations implicate a neurocircuit in which PACAP nociceptive signaling can impact stress-related behaviors. PACAP expression was induced along the spino-parabrachioamygdaloid tract in a partial sciatic nerve ligation chronic constriction injury (CCI) model of neuropathic pain. Amygdala PACAP infusions increased stress-related behaviors concomitant with heightened thermal nociceptive sensitivity, and conversely, CCI-induced behavioral and pain responses were attenuated upon acute amygdala PACAP receptor antagonist administration. Chronic pain increased amygdala ERK activation which could be mimicked by PACAP; notably, inhibition of PACAP receptor-mediated ERK signaling with drugs that block either MEK or endosomal signaling mitigated PACAP-mediated nociceptive hypersensitivity. Accordingly, PACAP signaling and function in the parabrachioamygdaloid tract may be a mediator of the adverse emotional consequences of chronic pain.