Response latencies in the tail-flick test depend on tail skin temperature

doi:10.1016/0304-3940(88)90497-1

Neuroscience Letters

Volume 86, Issue 3, 12 April 1988, Pages 284-288

https://doi.org/10.1016/0304-3940(88)90497-1 Get rights and content

Abstract

Tail skin temperatures and tail-flick latencies were simultaneously recorded in male Sprague-Dawley rats exposed to various ambient temperatures (22–30°C). There was a positive correlation between tail skin temperature and ambient temperature and a negative correlation between tail-flick latency and ambient temperature. Importantly, a highly significant negative correlation was present between tail-flick latency and skin temperature, even at constant ambient temperature (22.1 or 23.3°C). Thus, the results of tail-flick testing are highly affected by skin temperature and factors altering the skin temperature must be considered when tail-flick latencies are interpreted in terms of nociception.

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Hence, the analgesia in the hot plate test which is clearly apart from the acute antinociceptive effect of the neuropeptide given systemically [15] may involve opioidergic mechanisms in the rat’s brain as well. Conversely, it has been argued that the effect of oxytocin on nociception is indirectly mediated by a decrease in tail skin temperature caused by oxytocin [31]. However, tail temperature did not differ between oxytocin and saline treated rats when measured before the tail flick latency [17].
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The rostral ventromedial medulla (RVM) plays a key role in the endogenous modulation of nociceptive transmission in the central nervous system (CNS). The primary aim of this study was to examine whether the activities of RVM neurons were related to craniofacial nociceptive behaviour (jaw-motor response, JMR) as well as the tail-flick response (TF). The activities of RVM neurons and TF and JMR evoked by noxious heating of the tail or perioral skin were recorded simultaneously in lightly anaesthetized rats. Tail or perioral heating evoked the TF and JMR, and the latency of the JMR was significantly shorter (P < 0.001) than that of the TF. Of 89 neurons recorded in RVM, 40 were classified as ON-cells, 27 as OFF-cells, and 22 as NEUTRAL-cells based on their responsiveness to heating of the tail. Heating at either site caused an increase in ON-cell and decrease in OFF-cell activity before the occurrence of the TF and JMR, but did not alter the activity of NEUTRAL cells. Likewise, noxious stimulation of the temporomandibular joint had similar effects on RVM neurons. These findings reveal that the JMR is a measure of the excitability of trigeminal and spinal nociceptive circuits in the CNS, and that the JMR as well as TF can be used for studying processes related to descending modulation of pain. The findings also support the view that RVM ON- and OFF-cells play an important role in the elaboration of diverse nociceptive behaviours evoked by noxious stimulation of widely separated regions of the body.
Skin temperature contribution to the decrease in withdrawal latency following chronic constriction injury
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According to the above-mentioned findings, it seems possible that CCI increases skin temperature during the period of decreased withdrawal latency (as measured using the plantar test and 7–14 days after CCI). However, there is strong evidence that the withdrawal latency to thermal stimulation is inversely related to skin temperature [[5],[8],[20]]. Therefore the aim of this study was to (1) verify the increase in skin temperature after CCI, and, since skin temperature also depends on ambient temperature, we also decided to investigate whether (2) the skin temperature of the ligated limb was dependent on ambient temperature in the same manner as the contralateral limb when measured 11–14 days after surgery, and (3) whether withdrawal latency to thermal heat differs between the ligated and contralateral hind limb when they are, either artificially, using different ambient temperatures, or mathematically, using substitutions into a linear regression equation, at the same skin temperature.
Chronic constriction injury (CCI) is widely used as an animal neuropathic pain model. Neuropathic pain is considered to exist when withdrawal latency to thermal stimulation is decreased after inducing a CCI to the sciatic nerve. However, it is known that CCI leads to changes in skin temperature and that skin temperature can affect withdrawal latency. Aim of this study was to compare withdrawal latencies of constricted and contralateral hind limbs, to thermal stimulation, at the same artificially-induced skin temperatures.
Neuropathic pain was induced by four ligatures on the left sciatic nerve in adult male Wistar rats. Withdrawal latencies were measured from the 11th to 14th day after ligation, in different ambient temperatures, using the plantar test (Hargreaves method). By changing ambient we produced different hind limb skin temperatures.
Our results show that (1) CCI cause an increase in skin temperature; (2) the withdrawal latency was inversely related to ambient and skin temperature in the same manner for both the ligated and contralateral hind limbs; and (3) withdrawal latencies did not differ significantly for the ligated and contralateral hind limbs when the temperature of the hind limbs was artificially made the same (i.e., by changing the ambient temperature).
Withdrawal latencies to thermal stimulation did not differ on ligated and contralateral hind limb after CCI to the sciatic nerve if the temperature of the hind limbs was artificially or mathematically made the same. This finding may have significant impact on the interpretation results of neuropathic pain research.
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Ketamine which is widely used to manage neuropathic pain shows major limitations of low oral bioavailability (10–20%) and short half-life (<2 h), which affects the routine life style of patients (noncompliance due to multiple dosing and associated side effects). The current research aim to developed ketamine loaded Pluronic® F127 stabilized reduced graphene oxide hydrogel for sustain drug delivery via transdermal route. The Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray diffraction data confirm the attachment of Pluronic® F127 on the reduced graphene oxide. The scanning electron microscopy image showed the wrinkled and flattened nano-sheet surface with the presence of micelles. The ex vivo flux decreases proportionally with increase in the level of graphene oxide, which suggests that the ketamine release rate can be the tailored by changing the level of graphene oxide in the hydrogel. The writing test in mice confirmed low analgesic activity of ketamine loaded reduced graphene oxide hydrogel due to low flux rate of drug in comparison to control ketamine hydrogel (without graphene oxide). The tail-flick study on Wistar rats showed prolonged analgesic effect (24 h) with ketamine loaded reduced graphene oxide in comparison to ketamine control hydrogel (4 h). Thus, ketamine loaded Pluronic® F127-reduced graphene oxide hydrogel can be used to manage the neuropathic pain for the extended period of time bypassing associated side effects of intravenous, nasal and oral routes.
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Lidocaine is widely used as a local anaesthetic in the clinical practice to manage pre- and post-operative pain, skin burns, etc. However, the short duration of action (< 2 h) of marketed dosage forms limit their ability to meet clinical needs. Herein, we prepared a lidocaine-tPP(tri potassium phosphate)-complex loaded microemulsion to achieve greater penetration, followed by destabilization of microemulsion in the skin layer to precipitate oil-complex to produce a depot effect in the skin for prolonging the effects of anaesthesia. The lidocaine-tPP-complex-microemulsion was compared with lidocaine base loaded microemulsion, marketed ointment USP and lidocaine HCl. The pseudo ternary phase diagrams at three S_mix ratios (1:2, 1:3 and 1:4; Pluronic F127: PEG 400) were constructed using Capmul MCM C8 EP as oil phase. The S_mix at 1:4 ratio showed large microemulsion area in comparison to 1:2 and 1:6 ratio. The lidocaine base (LD-1:4-ME10O45SM and LD-1:4-ME20O45SM) and lidocaine-tPP-complex (LDC-1:4-ME10O45SM and LDC-1:4-ME20O45SM) loaded microemulsion batches (1:4 ratio) were thermodynamically stable. The ex vivo diffusion study showed sustained release up to 12 h with microemulsion batches, in comparison to lidocaine HCl (4 h) and ointment base (7 h). The selected LDC-1:4-ME20O45SM batch was non-irritating on the rabbit skin. In drug retention studies, LD-1:4-ME20O45SM and LDC-1:4-ME20O45SM batches showed 2.68- and 3.93-fold greater lidocaine retention in comparison to ointment USP. The radiant heat tail-flick test showed prolong local anaesthesia using LDC-1:4-ME20O45SM in comparison to ointment USP. The findings suggest that lidocaine-tPP-complex loaded microemulsion could be a potential strategy for providing prolong local anaesthesia.
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The present study aimed at investigating both the early and long-term effects of maternal deprivation as well as gender on neuromotor reflexes, anxiety behavior and thermal nociceptive responses. A total of 64 Wistar rats pups (32 males, 32 females) were utilized and were deprived of their mother for 3 h/daily, from postnatal day 1 (P1) until P10. Successively, animals were divided into 2 groups: control group (C) - pups no subjected to intervention; and the maternal-deprived group (MD): pups subjected to maternal deprivation. The neuromotor reflexes were evaluated through the righting reflex and negative geotaxis tests; the exploratory behavior by open field test (OFT); the anxiety-like behavior by elevated plus-maze test (EPM); the thermal nociceptive responses byhot plate (HP) and tail-flick (TFL) tests. All the animals subjected to maternal deprivation showed a delayed reflex response at P8 in the negative geotaxis test. In contrast, the OFT at P20 identified an effect of gender on the outer crossings and grooming as well as an interaction between gender and maternal deprivation on latency. Additionally, effect of maternal deprivation in the open and closed arms as well as gender effect in the protected head-dipping (PHD) and non-protected head-dipping (NPHD) were observed at P20 (EPM). In contrast, there were a gender effect on latency and an interaction between gender and maternal deprivation on rearing at P42. Moreover, in nociceptive tests was observed an analgesic effect induced by maternal deprivation; however, in the TFL test, only deprived females showed this effect. Surprisingly, only control animals presented an ontogeny nociceptive effect in the HP testat P21 and P43, which may be related to an increase in the inhibitory nociceptive pathways throughout life. In this way, we suggest maternal deprivation to be able to anticipate the maturation of the inhibitory nociceptive pathway. In conclusion, maternal deprivation induced a delayed reflex response at P8 and altered the anxiety and nociceptive behaviors according to the time after exposure to this stressor, in a gender-specific manner.

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Response latencies in the tail-flick test depend on tail skin temperature

Abstract

Brain Res.

Pain

Neuropharmacology

Life Sci.

Exp. Neurol.

Neurosci. Lett.

Brain Res.

Brain Res.

Pain