Involvement of the α7-nicotinic acetylcholine receptors in the anti-inflammatory action of the thymulin-related peptide (PAT)

Abstract

Background and purpose: Peptide analog of thymulin (PAT) has been shown to have anti-hyperalgesic and anti-inflammatory properties in animal models of inflammation. Recent reports suggest that the peripheral cholinergic system has an anti-inflammatory role mediated by α7-nicotinic acetylcholine receptor (α7-nAChR). Our aim is to investigate whether the action of PAT is mediated, via the cholinergic pathway.

Experimental approach: The anti-hyperalgesic and anti-inflammatory action of PAT was assessed in rat models of inflammatory nociceptive hyperactivity (carrageenan and endotoxin) and in a mice air-pouch model for localized inflammation, respectively; the possible attenuation of PAT's effects by pretreatment with the α7-nAchR specific antagonist methyllycaconitine citrate (MLA) was also investigated. In another series of experiments, using two electrode recordings, the effect of PAT on the α7-nAChRs, expressed in Xenopus Oocytes, was also determined.

Key results: Administration of PAT reversed inflammatory nociceptive hyperactivity and cold and tactile hyperactivity in rats. This effect was partially or totally prevented by MLA, as assessed by different behavioral pain tests. Treatment with PAT also reduced the alteration of cytokines and NGF levels by carrageenan injection in the mouse air pouch model; this effect was partially antagonized by MLA. Electrophysiological recording demonstrated that PAT significantly potentiated the α7-nAchR expressed in Xenopus Oocytes. These effects were not observed when a control peptide, with a reverse sequence (rPAT), was utilized.

Conclusions and implications: The behavioral and electrophysiological observations described in this report demonstrate that PAT mediates, at least partially, its anti-inflammatory action by potentiating the α7-nAChR. These results indicate that PAT has a potential for new therapeutic applications as anti-inflammatory and analgesic agent.

Keywords: 1,2-bis (o-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid; 4-(2-hydroxyethyl) piperazineethanesulfonic acid; ANOVA; Ach; BAPTA; ELISA; ET; HEPES; HP; ICV; IL; MBS; MLA; NGF; PAT; PWD; acetylcholine; analysis of variance; cytokines; endotoxin; enzyme-linked immunosorbent assay; hot plate; inflammation; interleukin; intracerebroventricular; methyllycaconitine citrate; modified Barth’s solution; nerve growth factor; nicotinic receptor antagonists; nicotinic receptors; nociceptive hyperactivity; paw withdrawal duration; peptide analog of thymulin; rPAT; reverse sequence of PAT; α7-nAChR; α7-nicotinic acetylcholine receptor.