Amygdala, neuropeptides, and chronic pain-related affective behaviors

Abstract

Neuropeptides play important modulatory roles throughout the nervous system, functioning as direct effectors or as interacting partners with other neuropeptide and neurotransmitter systems. Limbic brain areas involved in learning, memory and emotions are particularly rich in neuropeptides. This review will focus on the amygdala, a limbic region that plays a key role in emotional-affective behaviors and pain modulation. The amygdala is comprised of different nuclei; the basolateral (BLA) and central (CeA) nuclei and in between, the intercalated cells (ITC), have been linked to pain-related functions. A wide range of neuropeptides are found in the amygdala, particularly in the CeA, but this review will discuss those neuropeptides that have been explored for their role in pain modulation. Calcitonin gene-related peptide (CGRP) is a key peptide in the afferent nociceptive pathway from the parabrachial area and mediates excitatory drive of CeA neurons. CeA neurons containing corticotropin releasing factor (CRF) and/or somatostatin (SOM) are a source of long-range projections and serve major output functions, but CRF also acts locally to excite neurons in the CeA and BLA. Neuropeptide S (NPS) is associated with inhibitory ITC neurons that gate amygdala output. Oxytocin and vasopressin exert opposite (inhibitory and excitatory, respectively) effects on amygdala output. The opioid system of mu, delta and kappa receptors (MOR, DOR, KOR) and their peptide ligands (β-endorphin, enkephalin, dynorphin) have complex and partially opposing effects on amygdala function. Neuropeptides therefore serve as valuable targets to regulate amygdala function in pain conditions. This article is part of the special issue on Neuropeptides.

Keywords: Amygdala; CGPR; CRF; Opioids; Oxytocin; Pain; Vasopressin.

Figure 1. Site of action of neuropeptides in the amygdala circuitry related to pain processing.

The amygdala regions relevant to pain processing include basolateral nucleus (BLA), intercalated cells (ITC), and central nucleus (CeA) with its medial (CeM) and lateral and capsular (CeLC) divisions. Nociceptive input reaches the amygdala from the external lateral parabrachial area (PB) in the brainstem, targeting PKCδ, SOM and CRF neurons, but CGRP containing PB afferents contact mainly PKCδ and CRF rather than SOM neurons; SOM neurons also express only low levels of CGRP receptors (indicated by the dashed line). Polymodal including nociceptive information reaches the amygdala from sensory cortical and thalamic areas. Different cell types containing excitatory and inhibitory neuropeptides and/or receptors are shown. Output neurons with known projections to brain/brainstem regions outside the amygdala include SOM and CRF neurons mainly in the lateral CeA as well as CeM neurons. CeA neurons are mostly GABAergic (in red) and many co-express neuropeptides that can be excitatory (green) or inhibitory (red).