Investigation of the presence and antinociceptive function of muscarinic acetylcholine receptors in the African naked mole-rat (Heterocephalus glaber).

Kristine B Jørgensen,Darryl S Pickering,Klas S P Abelson,Titus I Kanui,Karen Krogh-Jensen

doi:10.1007/s00359-015-1048-x

Abstract

The present study investigated the cholinergic system in the African naked mole-rat (Heterocephalus glaber) with focus on the muscarinic acetylcholine receptor subtypes M1 and M4. The protein sequences for the subtypes m1–5 of the naked mole-rat were compared to that of the house mouse (Mus musculus) using basic local alignment search tool (BLAST). The presence and function of M1 and M4 was investigated in vivo, using the formalin test with the muscarinic receptor agonists xanomeline and VU0152100. Spinal cord tissue from the naked mole-rat was used for receptor saturation binding studies with [3H]-N-methylscopolamine. The BLAST test revealed 95 % protein sequence homology showing the naked mole-rat to have the genetic potential to express all five muscarinic acetylcholine receptor subtypes. A significant reduction in pain behavior was demonstrated after administration of 8.4 mg/kg in the formalin test. Administration of 50 mg/kg VU0152100 resulted in a non-significant tendency towards antinociception. The antinociceptive effects were reversed by the muscarinic acetylcholine receptor antagonist atropine. Binding studies indicated presence of muscarinic acetylcholine receptors with a radioligand affinity comparable to that reported in mice. In conclusion, muscarinic acetylcholine receptor subtypes are present in the naked mole-rat and contribute to antinociception in the naked mole-rat.

Highlights

Chronic pain is a major challenge in pain research and medicine, since it is often multifactorial and very difficult to treat (Pergolizzi et al 2012)
Using GenBank data from the National Center for Biotechnology Information (NCBI), the accession numbers and amino acid sequences encoded by m1–m5 in the house mouse (Mus musculus) and in the naked mole-rat were obtained
Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are essential when it comes to treating moderate to severe pain (Angst and Clark 2006), but adverse effects are seen with both (Kaminaga et al 1999; Pergolizzi et al 2012)

Summary

Introduction

Chronic pain is a major challenge in pain research and medicine, since it is often multifactorial and very difficult to treat (Pergolizzi et al 2012). Novel treatment strategies against chronic pain are desirable, and in the search for such treatments, the use of experimental animal models is necessary. The involvement of the muscarinic cholinergic receptor system in antinociception is well established. Antinociceptive effects of cholinomimetic drugs, such as oxotremorine (George et al 1962; Harris et al 1969; Ireson 1970; Bartolini et al 1987), pilocarpine (Hendershot and Forsaith 1959), physostigmine (Harris et al 1969; Ireson 1970), tremorine, arecoline and diisopropylphosphorofluoridate (DEP) have been investigated in different laboratory animal species (Bartolini et al 2011).

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