Activation of mu, delta or kappa opioid receptors by DAMGO, DPDPE, U-50488 or U-69593 respectively causes antinociception in the formalin test in the naked mole-rat (Heterocephalus glaber)

Abstract

Data available on the role of the opioid systems of the naked mole-rat in nociception is scanty and unique compared to that of other rodents. In the current study, the effect of DAMGO, DPDPE and U-50488 and U-69593 on formalin-induced (20 μl, 10%) nociception were investigated. Nociceptive-like behaviors were quantified by scoring in blocks of 5 min the total amount of time (s) the animal spent scratching/biting the injected paw in the early (0–5 min) and in the late (25–60 min) phase of the test. In both the early and late phases, administration of 1 or 5 mg/kg of DAMGO or DPDPE caused a naloxone-attenuated decrease in the mean scratching/biting time. U-50488 and U-69593 at all the doses tested did not significantly change the mean scratching/biting time in the early phase. However, in the late phase U-50488 or U-69593 at the highest doses tested (1 or 5 mg/kg or 0.025 or 0.05 mg/kg, respectively) caused a statistically significant and naloxone-attenuated decrease in the mean scratching/biting time. The data showed that mu, delta or kappa-selective opioids causes antinociception in the formalin test in this rodent, adding novel information on the role of opioid systems of the animal on pain regulation.

Introduction

Although nociception is fundamental to all animals, it has not been studied well in lower vertebrates such as the naked mole-rat. Naked mole-rats are primitive poikilothermic mammals found in semi-arid areas of Eastern Africa. They are subterranean rodents whose physiology is rather unique and interesting. Compared to other rodents of similar size, naked mole-rats have long life span (> 28 years) (Buffenstein, 2005). They are virtually blind and on their skin are vibrissae-like hairs that are useful for underground locomotion. They have prominent incisors and tactile hairs, both of which have large representation in the somatosensory cortex (Catania and Remble, 2002, Crish et al., 2003, Park et al., 2003, Henry et al., 2006).

Research on the nervous system of the naked mole-rat has shown that its skin lacks substance P- and calcitonin gene-related peptide- (CGRP) immunoreactive fibers (Park et al., 2003). Substance P and CGRP are among other neuropeptides involved in pain transmission and are up-regulated in response to noxious peripheral stimulation in rats (Zhang et al., 1994). The absence of SP and CGRP in the skin of the naked mole-rat raises queries on how this primitive rodent responds to noxious stimuli. Detailed study of its skin innervations revealed numerous non-peptidergic C-fibers, A-δ fibers and lanceolate endings supplied by Aβ fibers containing SP and CGRP (Park et al., 2003). The abundance of these fibers may suggest that they are crucial in nociception in this fossorial rodent. Aβ fibers are low threshold mechanoreceptors (Gottschaldt et al., 1973) but may also act as nociceptive fibers (Djouhri et al., 1998, Djouhri and Lawson, 2004).

Investigations on the roles of opioid systems of the naked mole-rat have also revealed some peculiarities. In the hot plate test (60 °C) Kanui and Hole (1990) reported that morphine caused aggression instead of analgesia. In a later study, we reported increased pain sensitivity in the hot plate test (60 °C) after acute administration of pethidine (Towett and Kanui, 1993). These reports suggested that the opioid drugs used had no analgesic effects but instead were pronociceptive in the hot plate test in this animal. However, studies performed using the formalin test in the same species of rodent demonstrated analgesic effects of morphine (Kanui et al., 1993) and codeine (Karim et al., 1993). This suggests a difference in the roles of opioid systems of the naked mole-rat on different kinds of pain. Such differences have also been documented in other rodents (Abbott et al., 1986).

The unique anatomy, behavior and physiology of the naked mole-rat make it very interesting for comparative studies of pain regulation. It is therefore essential to increase the knowledge about the nociceptive and antinociceptive responses in this particular species. Data available indicate that only morphine and codeine (mu agonists) have been tested for analgesia using the formalin test in the naked mole-rat (Kanui et al., 1993, Karim et al., 1993). To the best of our understanding, no report on the role of highly selective mu, delta or kappa opioid agonists in the formalin-induced pain in this animal is available. In a recent study, we reported that stimulation of mu or delta opioid receptors caused hyperalgesia while activation of kappa receptors caused antinociception in the hot plate test (Towett et al., 2006). In the light of these recent data, it is important to find out how receptor-selective opioids modulate formalin-induced pain in the naked mole-rat and how the data will compare with those of other rodents.

The aim of the present study was therefore to evaluate the effects of the mu [D-Ala²-NMePhe⁴-Gly-ol-enkephalin (DAMGO)], delta [D-Pen²-D-Pen⁵-enkephalin (DPDPE)], and kappa [trans(+)-3,4-Dichloro-N-methyl-N- [2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methane sulfonate (U-50488) and (5α,7α,8β)-(+)-N-Methyl-N- [7-(1-pyrrolidinyl)-1-oxaspirol[4.5]dec-8-yl]-benzeneacetamide (U-69593) receptor agonists on the formalin-induced pain in the naked mole-rat. In addition, the study aimed to verify the opioid-receptor involvement by attenuating antinociceptive effects with naloxone. The data collected suggest that mu- and delta-selective opioid agonists have antinociceptive effects in the formalin test contrary to what was earlier observed in the hot plate test (Towett et al., 2006) and provide additional knowledge on pain modulation by the opioid systems of the naked mole-rat.