Figure 3

Molecular actors in nociceptive processing in the CeA during arthritic pain. The CeA received nociceptive inputs from glutamatergic (Glu) neurons in the basolateral amygdala (BLA) and in the parabrachial nucleus (PB). GABAergic innervation originates from intrinsic source (CeA and BSTL) and from the intercalated cell masses (ITC). Additional modulation is provided by monoaminergic (MA) and cholinergic (ACh) afferents and by neuropeptides (Np), especially from CeA, BSTL and PB. These neuromediators act on excitatory (green) and inhibitory (red) receptors at pre and post-synaptic levels. In the knee monoarthritis model [5], several mechanisms contribute to a enhanced neurotransmission. At pre-synaptic level, mGluR1 receptors inhibit GABA release, while mGluR from groups II and III decrease glutamate release. At post-synaptic level, mGluR5 receptors are involved in normal transmission in naive animals and NMDA and AMPA ionotropic receptors have also an enhanced activity increasing neuronal sensitivity. CGRP, from PB, and CRF, possibly from the central extended amygdala itself, activate their post-synaptic receptors, CGRP1 and CRF1, respectively. These receptors can activate the protein kinase A (PKA) and thus increase NMDA phosphorylation. The extracellular regulated-signal kinase ERK also contributes to the sensitization of CeA neurons, possibly through a cascade initiated by mGluR5 receptors. CRF can also decrease the activity of CeA neurons, via pre-synaptic CRF2 receptors increasing GABA release. This leads to the inhibition of CeA neurons by activation of post-synaptic GABA A and GABA B receptors and by inhibition of glutamate release by pre-synaptic GABA B receptors. Other neurotransmission system involving noradrenergic (NA, especially through pre-synaptic α₂-receptors), dopaminergic (DA), serotonergic (5-HT) and cholinergic (ACh) receptors can modulate CeA activity, as well as other neuropeptides, among them opioids acting on pre- and post-synaptic mu receptors (MOR), and BDNF acting on TrkB receptors. Overall, these mechanisms lead to the modulation of the intra-CeA circuitry, based on GABAergic interactions (in blue) and of the CeA output.