A physiological study of Mu, delta and kappa opioid receptors in the naked Mole-rat (heterocephalus Gurer): Their roles in thermal and chemical nociception and behaviour

Abstract

The aims of this study were to investigate the following: (a) Antinociceptive effects of opioid receptor-selective drugs on thermal pain (Hot plate test) and chemical pain (Formalin test and Modified acetic acid test) and (b) Behavioural effects of opioid receptor-selective drugs in the naked mole-rat. The study was to provide data on the roles of specific opioid receptors (mu, delta and kappa) on nociception and sensorimotor behaviour in the naked mole-rat, a primitive fossorial rodent. In the hot plate test (60°C), DAMGO (mu-agonist) or DPDPE (delta agonist) caused a naloxone-reversible decrease in the response latency, whereas U-50488 or U-69593 (kappa agonists) caused a naloxone-reversible increase. in the response latency. .The effects of these drugs were dose- ~> dependant. Naloxonazine, a mu-l receptor antagonist blocked the effect of DAMGO on the response latency. In the formalin test (20 microliters, 10%), higher doses of DAMGO or DPDPE caused a statistically significant reduction in the mean scratchinglbiting time in both the early and late phases of the test. The effect was blocked by naloxone. Naloxonazine blocked the effect of DAMGO only in the late phase. U-50488 or U-69593, at all the doses used did not significantly change the mean scratchinglbiting time in the early phase. However, in the late phase higher doses of these drugs caused a statistically significant and naloxone-reversible decrease in the mean scratching/biting time. In the modified acetic acid test, a dose-dependent naloxone-reversible decrease in the mean wiping response was recorded following the administrationof DAMGO, DPDPE, U-50488 or U-69593. Naloxonazine also blockedthe effect of DAMGO in this test. On behaviour, DAMGO (> 1 mg/kg) caused a naloxone-reversible but not naloxonazine-reversible increase in motor activity, state of excitation and aggressivebehaviour. All the doses of DPDPE and lower doses ofU-50488 « 1 mglkg) or U-69593 « 0.05 mg/kg) used had no significant effect on the general behaviour of the animal. Higher doses of the kappa agonists caused an initial sensorimotor depression that gradually gave way to motor hyperactivity, excitationand aggression. The behavioural effects were dose-dependent. In summary, the current results clearly showed differences in the roles of opioid receptors on pain control and behaviour. DAMGO or DPDPE caused hyperalgesia in the hot plate test but antinociception in the formalin test and the modified acetic acid test, whereas-the kappa agonists (U-50488 or U- 69593) caused antinociception in all the three tests of nociception used in the naked mole-rat. These findings had not been reported before and therefore they provide more information on the roles of opioid system in the naked mole-rat. Both the hyperalgesia and the antinociception were mediated by opioid receptors as each was blocked by naloxone. It is possible that the NMethyl- Dsaspartate (NMDA) receptors in the central nervous system may be responsible for the opioid-induced hyperalgesia in naked mole-rat. Future use of NMDA receptor antagonists together with opioids may explain the mechanisms of the opioid-induced hyperalgesia in the naked mole-rat. The results also showed that the developed orofacial model of acetic acid test is a

useful model for studying nociception and antinociception in the naked molerat. Behavioural results showed that stimulation of kappa receptors produced, in a dose-dependent manner, an initial sensorimotor depression and later on marked excitation and aggression in the mole-rat, whereas stimulation of mu opioids caused enhanced motor activity when injected at high doses only. This suggested that kappa receptors could be crucial in initiating behavioural changes in the naked mole-rat. The mechanisms of opioid-induced behavioural effects are not clear at the moment. It is postulated that dopaminergic system may be responsible for the opioid-induced behaviour in the naked mole-rat. This is an area that needs to be investigated in future. It appears from the present data that the naked mole-rat may be a good model for studying opioid-induced tolerance and opioid-induced side effects commonly seen in cancer patients chronically treated with opioids .