Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors

Abstract

Amygdala plasticity is an important contributor to the emotionalaffective dimension of pain. Recently discovered neuropeptide S (NPS) has anxiolytic properties through actions in the amygdala. Behavioral data also suggest antinociceptive effects of centrally acting NPS, but site and mechanism of action remain to be determined. This is the first electrophysiological analysis of pain-related NPS effects in the brain. We combined whole cell patch-clamp recordings in brain slices and behavioral assays to test the hypothesis that NPS activates synaptic inhibition of amygdala output to suppress pain behavior in an arthritis pain model. Recordings of neurons in the laterocapsular division of the central nucleus (CeLC), which serves pain-related amygdala output functions, show that NPS inhibited the enhanced excitatory drive [monosynaptic excitatory postsynaptic currents (EPSCs)] from the basolateral amygdala (BLA) in the pain state. As shown by miniature EPSC analysis, the inhibitory effect of NPS did not involve direct postsynaptic action on CeLC neurons but rather a presynaptic, action potential-dependent network mechanism. Indeed, NPS increased external capsule (EC)-driven synaptic inhibition of CeLC neurons through PKA-dependent facilitatory postsynaptic action on a cluster of inhibitory intercalated (ITC) cells. NPS had no effect on BLA neurons. High-frequency stimulation (HFS) of excitatory EC inputs to ITC cells also inhibited synaptic activation of CeLC neurons, providing further evidence that ITC activation can control amygdala output. The cellular mechanisms by which ECdriven synaptic inhibition controls CeLC output remain to be determined. Administration of NPS into ITC, but not CeLC, also inhibited vocalizations and anxiety-like behavior in arthritic rats. A selective NPS receptor antagonist ([D-Cys(tBu) 5 ]NPS) blocked electrophysiological and behavioral effects of NPS. Thus NPS is a novel tool to control amygdala output and pain-related affective behaviors through a direct action on inhibitory ITC cells. amygdala; pain behavior; neuropeptide S; synaptic transmission NEUROPLASTICITY in the amygdala network of lateral-basolateral (LA-BLA) and central (CeA) nuclei has emerged as an important contributor to emotional-affective aspects of pain (Neugebauer et al.

Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model

“…Target concentrations of MMF were reported to be in the range of 10–30 μM, with 15 μM being tested most commonly although 5 μM was used occasionally [1;3;49;58]. For microdialysis drug application we used 1 mM because a 100 fold higher concertation is needed inside the probe due to the concentration gradient across the microdialysis membrane as indicated by our own work comparing drug effects in brain slices with microdialysis drug application for a variety of compounds [12;31;36;46]. For systemic application, DMF and MMF have been shown to be effective at doses of 15, 25, 30 and 50 mg/kg whereas 5 mg/kg was not effective consistently [1;7;49;51;56].…”

“…Due to the concentration gradient across the microdialysis membrane a 100 fold higher concertation is needed inside the probe [12;31;36;46], and so we used 1 mM. For systemic application, DMF and MMF have been shown to be effective at doses of 15, 25, 30 and 50 mg/kg whereas 5 mg/kg was not effective consistently [1;7;49;51;56].…”

Nasal Application of Neuropeptide S Inhibits Arthritis Pain-Related Behaviors through an Action in the Amygdala

“…The elevated plus-maze (Columbus Instruments) was used as described previously [29]. The EPM has two enclosed and two open arms that are arranged in a plus shape.…”

“…Intracerebroventricular administration of NPS also had antinociceptive effects in the tail-flick, hot-pate and formalin tests [34,35], and we showed recently that direct application of NPS into the ITC inhibited emotional-affective responses in an arthritis pain model [29]. Importantly, recent evidence suggests that NPS can be administered nasally to exert anxiolytic effects [36,37].…”

Endogenous neuropeptide S tone influences sleep–wake rhythm in rats

“…Neuropeptide S also decreased diazepam-induced sleep time in mice. The NPSR could be involved in this NPS effect because it is counteracted by the selective NPSR antagonist, [D-Cys(tBu)5]NPS blocked these pain-induced electrophysiological and behavioral effects of NPS [20].…”