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Comparative studies using reptiles as experimental animals in pain research could expand our knowledge on the evolution and adaptation of pain mechanisms. Currently, there are no data reported on the involvement of voltage-gated sodium ion channels on nociception in reptiles. The aim of this study was to investigate the involvement of Nav1.3, Nav1.7, and Nav1.8 ion channels in nociception in Speke's hinge-back tortoise. ICA 121341 (selective blocker for Nav1.1/Nav1.3), NAV 26 (selective blocker for Nav1.7), and A803467 (selective blocker for Nav1.8) were used to investigate the involvement of Nav1.3, Nav1.7, and Nav1.8, respectively. The chemicals were administered intracoelomically thirty minutes before the start of nociceptive tests. ICA 121341 did not cause a significant decrease in the time spent in pain-related behavior in all the nociceptive tests. NAV 26 and A8034667 caused a statistically significant decrease in the mean time spent in pain-related behavior in the formalin and capsaicin tests. Only A803467 caused a statistically significant increase in the mean latency to pain-related behavior in the hot plate test. NAV 26 and A803467 had no observable side effects. In conclusion, Nav1.7 and Nav1.8 are involved in the processing of chemically induced inflammatory pain in Speke's hinge back tortoise. In addition, Nav1.8 are also significantly involved in the development of thermal-induced pain-related behavior in this species of reptile. However, our results do not support the involvement of Nav1.3 on the development of chemical or thermal induced pain-related behavior in the Speke's hinge back tortoise., (© 2023 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Some of the most commonly used analgesic drugs in animals are of questionable efficacy or present adverse side effects among the various species of reptiles. Tricyclic antidepressants have been demonstrated to have antinociceptive effects in several animal models of pain and could be a good alternative for use in reptiles. The aim of the study was to investigate the antinociceptive effects of nortriptyline and desipramine hydrochloride in Speke's hinge-back tortoise. A total of 24 animals weighing 600-1000 g were used for nociceptive tests, i.e., formalin, capsaicin, and hot plate tests. Drugs were administered intracoelomically 30 min before starting the tests. The time spent in nocifensive behavior and the associated observable effects during the tests were recorded. Only the highest dose of 40 mg/kg of nortriptyline hydrochloride caused statistically significant decrease in nocifensive behavior in both the formalin and the capsaicin test. Desipramine hydrochloride at doses of 20 and 40 mg/kg caused statistically significant decrease in nocifensive behavior in the formalin test. Also, desipramine hydrochloride at doses of 15, 20, and 60 mg/kg caused statistically significant decrease in nocifensive behavior in the capsaicin test. None of the doses used for both drugs had any statistically significant effect on nocifensive behavior in the hot plate test. The results show that nortriptyline and desipramine hydrochloride have significant antinociceptive effects in the chemical but not thermal inflammatory pain-related behavior in the Speke's hinge-back tortoise. The most common associated side effect following administration of the higher doses of either of the drugs is excessive salivation., (© 2023 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

The naked mole rat (NMR) is a fossorial rodent that has been observed to have a unique nociceptive system in comparison to others. In this study, we explored on characterization of chronic inflammation in the NMR using Complete Freund's adjuvant (CFA) and investigated the effects of dexamethasone and acetylsalicylic acid on the resulting inflammation. The NMRs were injected with 0.1 ml of CFA subcutaneously in the right hind paw, and an equivalent volume of normal saline was injected to the control group. Swelling of the injected right hind limb was observed within 24 h of injection, which involved the tibiotarsal joint, palmar surface and the digits of the injected paw. Swelling persisted for 6 weeks of experimentation and peaked between day 14 and 21. The resulting inflammation affected the mobility, stance and joint rigidity of CFA treated NMRs in comparison to the control group. Treatment of the chronic phase of the inflammation from the 11 th day with dexamethasone and acetylsalicylic acid showed no statistical significance in paw circumference compared to the control group, other than on a few, negligible occasions. The present data showed that CFA was able to induce chronic inflammation in the NMR, and the NMR could thus be established as a model for chronic inflammation. There is, however, need for more sensitive parameters to evaluate the effects of anti-inflammatory drugs., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Background: There are limited studies on the utilization of analgesics in testudines. Management of pain in reptiles is by use of analgesics generally used in other vertebrate species. Evidently, some analgesics considered to be generally effective in reptiles are not effective in certain reptile species., Objective: The purpose of this study was to examine the effect of amitriptyline hydrochloride on nociceptive behaviour in Speke's hinge-back tortoise., Methods: Twenty-four adult Speke-hinged tortoises weighing 500-700 g were used. The effects of amitriptyline hydrochloride on nociception were evaluated using the formalin, capsaicin and hot plate nociceptive tests. Amitriptyline was administered intracoelomically at doses of 0.5, 1.0 and 3.0 mg/kg., Results: The higher doses of amitriptyline hydrochloride caused an increase in nociceptive behaviour (time spent in hindlimb withdrawal) on the formalin and capsaicin nociceptive tests, suggesting a potentiating effect. However, the doses used had no significant change in nociceptive behaviour on withdrawal response in the hot plate test., Conclusions: The study showed that amitriptyline hydrochloride which is widely used in management of neuropathic pain potentiates nociceptive effects in the formalin and capsaicin nociceptive tests in the Speke's hinge-back tortoise. The hot plate test, which previously has not been reported in these animals, gave results not in line with the other tests and therefore more testing and validation of the test is required. Amitriptyline modulates chemical and thermal pain differently., (© 2021 The Authors Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

The study was designed to investigate the involvement of noradrenergic and serotonergic receptor systems in the modulation of formalin-induced pain-related behaviour in the Speke's hinged tortoise. Intradermal injection of 100 μL of formalin at a dilution of 12.5% caused pain-related behaviour (hindlimb withdrawal) that lasted for a mean time of 19.28 min (monophasic response). Intrathecal administration of clonidine (α 2 -adrenergic receptor agonist) and yohimbine (α 2 -adrenergic receptor antagonist) at a dose of 40 μg/kg and 37.5 μg/kg or 50 μg/kg, respectively, caused a highly significant reduction in the duration of the formalin-induced pain-related behaviour. The effect of clonidine was reversed by intrathecal administration of yohimbine at a dose of 26.7 μg/kg. The effect of yohimbine at a dose of 50 μg/kg was reversed by intrathecal injection of 20 μg/kg of the serotonergic receptor antagonist methysergide maleate. When performing antagonistic reactions, the administration of the antagonist was followed immediately by that of the agonist. The study indicates that for experimental purposes, intrathecal route of drug administration through the atlanto-occipital joint is effective in tortoises. The data also suggest that testudines have noradrenergic and serotonergic systems that appear to play a role in the modulation of pain in this species., (© 2016 John Wiley & Sons Ltd.)

Background: The role of noradrenergic system in the control of nociception is documented in some vertebrate animals. However, there are no data showing the role of this system on nociception in the marsh terrapins., Methodology: In this study, the antinociceptive action of intrathecal administration of the α 2-adrenoreceptor agonist clonidine and α 2-adrenoreceptor antagonist yohimbine was evaluated in the African marsh terrapin using the formalin test. The interaction of clonidine and yohimbine was also evaluated., Results: Intrathecal administration of clonidine (37.5 or 65 μg/kg) caused a significant reduction in the mean time spent in pain-related behavior. Yohimbine, at a dose of 25 μg/kg, significantly blocked the effect of clonidine (65 μg/kg). However, administration of yohimbine (40 or 53 μg/kg) caused a significant reduction in the mean time spent in pain-related behavior. Intrathecal administration of yohimbine (53 μg/kg) followed immediately by intrathecal injection of the serotonergic methysergide maleate (20 μg/kg) resulted in a significant reversal of the antinociceptive effect of yohimbine., Conclusion: The present study documented the intrathecal administration of drugs in the marsh terrapin, a technique that can be applied in future studies on these animals. The data also suggest the involvement of both α 2-adrenoreceptors and 5HT receptors in the modulation of nociception in testudines.

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.

Little is known about analgesia in lower vertebrates such as the Speke's hinged tortoise (Kinixy's spekii), yet of late they are increasingly being adopted as pets. The effects of morphine (5, 7.5, 10 and 20 mg/kg), pethidine (10, 20, and 50 mg/kg) and naloxone (5 mg/kg) on nociception induced by the formalin test (12.5%, 100 microL) were studied in the Speke's hinged tortoise. Formalin induced a monophasic limb retraction behavioural response and its duration was recorded. The behaviour lasted for 16.4 +/- 0.8 min. Morphine (7.5, 10 and 20 mg/kg) and pethidine (20 and 50 mg/kg) induced significant decrease in the duration of limb retraction in the formalin test. The anti-nociceptive effects were naloxone (5 mg/kg) reversible. The data suggest that the formalin test is a good test for studying nociception and anti-nociception in tortoises and that the opioidergic system plays a role in the control of nociception in these animals.

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 microl, 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.

Comparative investigations were made between wild and domestic ruminants from arid and semi-arid regions and those species from non-arid areas in an attempt to evaluate the adaptations of these ruminants in terms of the effects of heat stress and dehydration on food intake and digestibility. The effect of (a) an intermittent heat load (a daily light cycle of 12 h at 22 degrees C and 12 h at 40 degrees C) compared to 22 degrees C throughout the day and (b) dehydration level of 15% weight loss, with and without the heat load, on the intake and digestibility of a poor quality hay was investigated in the Grant's gazelle, Oryx, the domestic Turkana goats, fat-tailed sheep, zebu cattle, Thomson's gazelle and wildebeest. The intermittent heat load with water available ad libitum depressed the food intake of zebu cattle and Turkana goats by more than 40%. It had no significant effect on the food intake of the other species. The Thomson's and Grants gazelle, oryx, wildebeest and fat-tailed sheep appear well adapted to withstanding a periodic heat load. Dehydration at 22 degrees C caused a marked depression on food intake of all the species investigated. Dehydration together with a heat load caused no further reduction in the food intake by the Grants's gazelle, oryx, and goats but it did cause a further reduction in the intake in the other species. The small non-domestic ruminants (i.e. Grant's and Thomson's gazelle) appear much more digestive efficient than any of their domestic counterpart.

The antinociceptive effects of highly selective mu (DAMGO), delta (DPDPE) and kappa (U-50488 and U-69593) opioid agonists were evaluated following intraperitoneal (i.p.) administration in the naked mole-rat. A hot plate test set at 60 degrees C was used as a nociceptive test and the latency to the stamping of the right hind paw (response latency) was used as the end-point. DAMGO (5-10 mg/kg) and DPDPE (2.5-5 mg/kg) caused a naloxone-reversible significant decrease in the mean response latency. Subcutaneous injection of naloxonazine (20 mg/kg) 24h prior to the administration of DAMGO (5 mg/kg) also blocked the reduction in the response latency observed when DAMGO was injected alone. On the contrary, U-50488 (2.5-5 mg/kg) or U-69593 (0.08 or 0.1 mg/kg) caused a naloxone-reversible significant increase in the mean response latency. These results showed that activation of mu or delta receptors caused hyperalgesia, whereas activation of kappa receptors caused antinociception in the hot plate test in naked mole-rat. This suggests that mu and delta receptors modulate thermal pain in a different way than kappa receptors in the naked mole-rat. It is not possible at the moment to point out how they modulate thermal pain as little is known about the neuropharmacology of the naked mole-rat.

The antinociceptive and behavioral effects of pethidine (10, 20, or 30 mg/kg), acetylsalicylic acid (200, 400, or 600 mg/kg) and indomethacin (20, 40, or 50 mg/kg) in the naked mole-rat was studied in the hot-plate test. Instead of inducing analgesia, pethidine caused a dose-dependent reduction in response latency. Sensorimotor impairment and aggressive behavior were also observed following administration of pethidine (20 or 30 mg/kg). All animals receiving pethidine (30 mg/kg) died following fighting when kept in colony cages. Aggressive behavior and death was prevented by naloxone or by keeping animals in single cages. Acetylsalicylic acid (600 mg/kg) and indomethacin (40 or 50 mg/kg) caused a significant increase in response latency. It is concluded that in the mole-rat pethidine elicits aggression, sensorimotor impairment, and apparent hyperalgesia.

The present experiments were initiated to study the effects of morphine, nefopam and paracetamol in the naked mole-rat, a hairless rodent that lives in subterranean colonies of up to 300, following the inability to demonstrate morphine analgesia in the hot-plate test in the rodent. The formalin test was used. Injection of 20 microliters 10% formalin produced two periods of high licking and pain behaviour, the early (0-5 min) and the late phase (15-60 min). Morphine (10 or 20 mg/kg), nefopam (10 or 20 mg/kg) and paracetamol (200 mg/kg) significantly inhibited the two phases. Paracetamol (400 mg/kg) produced significant analgesia only during the late phase. It is concluded that, unlike in the hot-plate test, it is possible to demonstrate the analgesic effects of morphine in the naked mole-rat, in the formalin test.