The effects of oxotremorine, epibatidine, atropine, mecamylamine and naloxone in the tail-flick, hot-plate, and formalin tests in the naked mole-rat (Heterocephalus glaber).

The naked mole-rat (Heterocephalus glaber) is a promising animal model for the study of pain mechanisms, therefore a thorough characterization of this species is essential. The aim of the present study was to establish the naked mole-rat as a model for studying the cholinergic receptor system in antinociception by investigating the involvement of muscarinic, nicotinic and opioid receptors in nociceptive tests in this species. The effects of systemic administration of the muscarinic receptor agonist oxotremorine and the nicotinic receptor agonist epibatidine were investigated in the tail-flick, the hot-plate, and the formalin tests. The effects of co-administration of the muscarinic receptor antagonist atropine, the nicotinic receptor antagonist mecamylamine, and the opioid receptor antagonist naloxone were also investigated. Oxotremorine and epibatidine induced a significant, dose-dependent antinociceptive effect in the tail-flick, hot-plate, and formalin tests, respectively. The effects of oxotremorine and epibatidine were blocked by atropine and mecamylamine, respectively. In all three nociceptive tests, naloxone in combination with oxotremorine or epibatidine enhanced the antinociceptive effects of the drugs. The present study demonstrated that stimulation of muscarinic and nicotinic receptors produces antinociceptive effects in the naked-mole rat. The reversal effect of atropine and mecamylamine suggests that this effect is mediated by cholinergic receptors. As naloxone increases the antinociceptive effects of cholinergic agonists, it is suggested that the cholinergic antinociception acts via a gateway facilitated by opioid receptor blockage; however, the precise interaction between these receptor systems needs further investigation. The naked mole-rat (Heterocephalus glaber) is an animal that is gaining increasing interest as a model for human diseases such as cancer, aging, hypoxia, and pain (1-4). Pain is one of the foremost causes of suffering in humans, as well as in animals, and there is a well-acknowledged need for improved treatments against pain (5, 6). Although numerous animal models for various pain conditions exist, these are not sufficient at present to solve the challenges in discovering novel pain therapies, which is why there is a need for developing new animal models in pain research. The use of animal species of different phylogeny may increase the knowledge of the evolution of the nociceptive system, and thus increase our understanding of the pharmacological and physiological mechanisms that regulate nociception and painrelated behavior (7). Thorough characterization of nociceptive mechanisms in different species is, thus, important. The naked mole-rat is a sub-terranean rodent belonging to the family Bathyergidae. It is considered an interesting animal model for nociceptive mechanisms, as its nociceptive system has been shown to differ from that of other mammals. It has been reported that the animal completely lacks cutaneous Cfibre immunoreactive to substance P and calcitonin generelated peptide (GRRP) (2, 3). In the hot-plate test, the animals were found to display aggressive behavior and hyperalgesia, instead of analgesia, when treated with morphine or pethidine (8, 9). This appears to be related to different properties of μ-, δand κ-receptors in mole-rats compared to other rodents (10). In the formalin test, however, stimulation with μ-, κad δ-opioid receptor agonists resulted in antinociceptive effects (11). The antinociceptive effects of non-steroidal and steroidal anti-inflammatory drugs have also been investigated in this animal (12, 13). Other receptor systems, including the cholinergic receptor system, are known to be involved in nociceptive regulation and have been extensively investigated in other animal 39 Correspondence to: Klas Abelson, Associate Professor, Ph.D., University of Copenhagen, Department of Experimental Medicine, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. Tel: +45 35326272, Fax: +45 35327399, e-mail: klasab@sund.ku.dk