Intra-amygdala microinfusion of neuropeptide S attenuates neuropathic pain and suppresses the response of spinal microglia and astrocytes after spinal nerve ligation in rats

• Neuropeptide S (NPS) and its receptor are involved in the development of neuropathic pain (NP).
• Chronic microinjection of NPS into the amygdala could inhibit pain behaviors induced by spinal nerve ligation (SNL).
• Intra-amygdala microinfusion of NPS suppressed the response of spinal microglia and astrocytes after SNL.
• NPS microinjection into amygdala inhibited the inflammatory reaction in SNL rats.

The amygdala circuitry and neuropeptide S (NPS) have been shown to play an important role in the pain modulation. However, the alleviative effect of NPS in amygdala on neuropathic pain (NP) is not fully understood. Here, we demonstrate a possibility that the intra-amygdala microinfusion of NPS attenuates NP symptoms and suppresses the response of spinal microglia and astrocytes after spinal nerve injury. Spinal nerve ligation (SNL) in rats resulted in a striking decline in level of NPS and density of NPS-immunopositive cells in amygdala. SNL rats randomly received chronic bilateral microinjections of NPS (1, 10 and 100 pmol/side) or saline into the amygdala via cannulas on days 3, 6, 9, 12, 15 and 18 post-surgery. Chronic treatment with NPS increased thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) on day 11–21 post-SNL. The simultaneous treatment with SHA68 as non-peptide NPS receptor antagonist decreased the TWL and MWT, and reversed the inhibitory effects of NPS in SNL rats. NPS also significantly attenuated immunoreactivities of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein for microglia and astrocytes. Furthermore, the elevated levels of inflammatory mediators and expressions of nuclear factor κB p65 and CX3C chemokine receptor 1 due to SNL were significantly attenuated by NPS in amygdala. These effects of NPS were also counteracted by SHA 68. SHA 68 per se deteriorated the symptom of NP and the response of spinal microglia and astrocytes in SNL rats. Our study identified a protective role for NPS in amygdala against the development of NP, possibly attributing to its anti-inflammatory activity and inhibition of spinal microglia and astrocytes.