Monoamines and neuropeptides interact to inhibit aversive behaviour in Caenorhabditis elegans

Pain modulation is complex, but noradrenergic signalling promotes anti-nociception, with alpha(2)-adrenergic agonists used clinically. To better understand the noradrenergic/peptidergic modulation of nociception, we examined the octopaminergic inhibition of aversive behaviour initiated by the Caenorhabditis elegans nociceptive ASH sensory neurons. Octopamine (OA), the invertebrate counterpart of norepinephrine, modulates sensory-mediated reversal through three alpha-adrenergic-like OA receptors. OCTR-1 and SER-3 antagonistically modulate ASH signalling directly, with OCTR-1 signalling mediated by G alpha(o). In contrast, SER-6 inhibits aversive responses by stimulating the release of an array of 'inhibitory' neuropeptides that activate receptors on sensory neurons mediating attraction or repulsion, suggesting that peptidergic signalling may integrate multiple sensory inputs to modulate locomotory transitions. These studies highlight the complexity of octopaminergic/peptidergic interactions, the role of OA in activating global peptidergic signalling cascades and the similarities of this modulatory network to the noradrenergic inhibition of nociception in mammals, where norepinephrine suppresses chronic pain through inhibitory alpha(2)-adrenoreceptors on afferent nociceptors and stimulatory alpha(1)-receptors on inhibitory peptidergic interneurons. The EMBO Journal (2012) 31, 667-678. doi: 10.1038/emboj.2011.422; Published online 29 November 2011