Role of CGRP in the amygdala in pain-related synaptic plasticity and behavior

Pain has a strong emotional component. In particular, arthritic pain is closely related to affective disorders such as anxiety and depression. A key player in the emotional evaluation of sensory stimuli, the amygdala has been suggested as a neural substrate of the reciprocal relationship between pain and affect. Nociceptive information reaches the central nucleus of the amygdala (CeA) through the spino-parabrachio-amygdaloid pain pathway and spino-amygdaloid connections. Highly processed polymodal information from thalamo-cortical areas is transmitted to the CeA through the lateral and basolateral amygdaloid nuclei. Previous studies have shown that CeA neurons undergo significant neuroplastic changes in a model of arthritic pain. \r\nImportantly, high levels of calcitonin gene-related peptide (CGRP) are present in the CeA, most notably in the latero-capsular part (CeLC), which is now defined as the "nociceptive amygdala". The parabrachio-amygdaloid connection is essentially the exclusive source of CGRP in the CeA. The role of CGRP in pain processing has been studied mainly in peripheral tissues and in the spinal cord. However, information about CGRP function in the brain is still limited. Moreover, the role of neuropeptides in synaptic plasticity is less well understood than that of classical transmitters such as glutamate. \r\nThe present study determined the role of CGRP in the amygdala at the cellular and systems levels, using an integrative approach that combines patch-clamp recordings in brain slices in vitro and analysis of spinally (withdrawal reflexes) and supraspinally (vocalizations) organized behavior in awake animals. A well-established preclinical animal model of arthritic pain induced by kaolin and carrageenan was used. Our results show that selective CGRP1 receptor antagonists (CGRP8-37 and BIBN4096NS) in the CeLC reverse arthritis pain-related plasticity and behavior through a PKA-dependent postsynaptic mechanism that involves NMDA receptors. In addition, exogenous CGRP application in the CeLC in naive animals mimics pain-related synaptic plasticity and behavior. Selective inhibitors of PKA and MEK (ERK1/2), but not PKC, inhibit pain-related synaptic plasticity and behavior in arthritic animals and CGRP-induced synaptic plasticity and behavior in naive animals. \r\nThis work shows for the first time the importance of CGRP as a critical link between amygdala plasticity and pain behavior. The results provide direct evidence that CGRP receptor activation in the amygdala contributes to pain-related synaptic plasticity in the amygdala through a postsynaptic mechanism that involves PKA, ERK1/2 and NMDA receptors. This plasticity results in spinally and supraspinally organized pain behavior.\r\n