GABAergic CaMKIIα+ Amygdala Output Attenuates Pain and Modulates Emotional-Motivational Behavior via Parabrachial Inhibition

Abstract

Pain and emotion are strongly regulated by neurons in the central nucleus of the amygdala (CeA), a major output of the limbic system; yet, the neuronal signaling pathways underlying this modulation are incompletely understood. Here, we characterized a subpopulation of CeA neurons that express the CaMKIIα gene (CeA^CAM neurons) and project to the lateral parabrachial nucleus (LPBN), a brainstem region known for its critical role in distributing nociceptive and other aversive signals throughout the brain. In male Sprague Dawley rats, we show that CeA^CAM-LPBN neurons are GABAergic and mostly express somatostatin. In anaesthetized rats, optogenetic stimulation of CeA^CAM-LPBN projections inhibited responses of LPBN neurons evoked by electrical activation of Aδ- and C-fiber primary afferents; this inhibition could be blocked by intra-LPBN application of the GABA_A receptor antagonist bicuculline. CeA^CAM-LPBN stimulation also dampened LPBN responses to noxious mechanical, thermal, and chemical stimuli. In behaving rats, optogenetic stimulation of CeA^CAM-LPBN projections attenuated nocifensive responses to mechanical pressure and radiant heat, disrupted the ability of a noxious shock to drive aversive learning, reduced the defensive behaviors of thigmotaxis and freezing, induced place preference, and promoted food consumption in sated rats. Thus, we suggest that CeA^CAM-LPBN projections mediate a form of analgesia that is accompanied by a shift toward the positive-appetitive pole of the emotional-motivational continuum. Since the affective state of pain patients strongly influences their prognosis, we envision that recruitment of this pathway in a clinical setting could potentially promote pain resilience and recovery.

SIGNIFICANCE STATEMENT Pain and emotion interact on multiple levels of the nervous system. Both positive and negative emotion may have analgesic effects. However, while the neuronal mechanisms underlying “stress-induced analgesia” have been the focus of many studies, the neuronal substrates underlying analgesia accompanied by appetitive emotional-motivational states have received far less attention. The current study focuses on a subpopulation of amygdala neurons that form inhibitory synapses within the brainstem lateral parabrachial nucleus (LPBN). We show that activation of these amygdalo-parabrachial projections inhibits pain processing, while also reducing behaviors related to negative affect and enhancing behaviors related to positive affect. We propose that recruitment of this pathway would benefit pain patients, many of whom suffer from psychological comorbidities such as anxiety and depression.