Monoamines and neuropeptides modulate neuronal plasticity and interact to define behavioral state in both vertebrates and invertebrates. In C. elegans, monoamines and peptides interact to modulate aversive responses mediated by the polymodal, nociceptive ASH sensory neurons, with serotonergic stimulation inhibited by octopamine (OA) (Wragg et al., 2007; Harris et al., 2009). In the present study, we have demonstrated that octopaminergic inhibition of ASH-mediated aversive responses is mediated by three different octopamine receptors, OCTR-1, SER-6 and SER-3, depending on the intensity of the initiating stimulus. At 30% octanol, OCTR-1 inhibits signaling in the ASHs directly through a Go dependent pathway and at 100% octanol, a second OA receptor SER-6, stimulates the release of peptides from the peptidergic ADL and AWB sensory neurons through a Gs/q dependent pathway. SER-3 opposes the action of OCTR-1 at higher exogenous OA concentrations. Specifically, the OA and SER-6 dependent release of peptides encoded by
nlp-7 and 8 from the ADLs and
nlp-9 from the AWBs is essential for maximal OA inhibition of aversive responses to 100% octanol. In contrast, overexpression of
nlp-7, 8 or 9 in wild type animals dramatically decreases basal aversive responses to 100% octanol, confirming an inhibitory role for these peptides. Receptors for peptides encoded by
nlp-7, 8 and 9 have been tentatively identified using an epigenetic approach, i.e., 1) animals with putative null alleles for these receptors are not inhibited by OA, 2) the overexpression of these receptors in wild type animals inhibits basal aversive responses, in a manner identical to the overexpression of the individual peptide encoding genes and 3) the overexpression of
nlp-7, 8 or 9 in these receptor null mutants does not inhibit basal aversive responses. These studies highlight the complexity of octopaminergic inhibition and the role of "inhibitory" neuropeptides in the modulation of aversive behaviors and are continuing to examine the role of the individual peptide receptors in sensory-mediated locomotory circuits.