Increase In Tail-flick Latency Research Articles

Comparisons between warm and cold water swim stress in mice

The following experiments evaluated the effects of warm- or cold-water swim stress on tail-flick latencies (TFL) in mice. To first determine the appropriete control group, the TFL's of dry-vs-dunked mice were compared. Dry mice had significantly shorter TFL's than dunked mice, implying that the dampness of the mouse's tail contributed to the increase in the TFL. Therefore, dunked mice were used as the relevant control for the swum mice. Cold water swimming (2°C) produced a significant increase in the TFL; this was not blocked by the opiate antagonist naloxone (3 mg/kg sc) or potentiated by the enkephalinase inhibitor thiorphan (100 mg/kg sc). Warm water swimming (32°C) up to 3 min produced an inconsistent effect on TFL's, implying that the effects were at the threshold of detectability. Naloxone attenuated and thiorphan modestly potentiated the effects of warm water swimming on TFL's. This suggests that warm water swim stress-induced increases in mouse TFL's may involve opioid pathways, whereas cold water swim stress-induced changes in mice TFL's appear not to be opioid mediated.

Antagonism of stimulation-produced antinociception by intrathecal administration of methysergide or phentolamine

This study examined whether the antinociception produced by electrical stimulation of medullary raphe nuclei is mediated by activation of monoaminergic neurons projecting to the spinal cord. Ninety-four sites distributed about the midline of the medulla were stimulated and their ability to produce antinociception was determined using two different analgesiometric tests. Stimulation of sites in the nuclei raphe pallidus and raphe obscurus did not produce antinociception, but rather, produced tremor and, on occasion, extensor rigidity. In contrast, stimulation at sites located in the nucleus raphe magnus and the adjacent nucleus reticularis paragigantocellularis produced antinociception, as indicated by increased tail flick latencies and decreased responsiveness to noxious pinch applied to the extremities. Intrathecal administration of saline prior to electrical stimulation of these sites did not attenuate either the elevation of tail flick latencies or the decreased responsiveness to pinch. However, intrathecal administration of 30 μg of either methysergide or phentolamine prior to stimulation at these same sites significantly attenuated the increase in tail flick latency and restored responsiveness to pinch. Naloxone (1 mg/kg, s.c.) did not attenuate the stimulation-produced antinociception evoked from any of these sites. These data support the postulate that the antinociceptive effect of electrical stimulation of the nucleus raphe magnus and the nucleus reticularis paragigantocellularis is mediated by activation of serotonergic and noradrenergic neurons projecting to the spinal cord. The inability of either methysergide or phentolamine alone to completely antagonize the elevation of tail flick latency further suggests that the serotonergic and noradrenergic bulbospinal systems are coactivated by electrical stimulation of these sites.

Effects of an intrathecal dopamine agonist, apomorphine, on thermal and chemical evoked noxious responses in rats

The thermal cutaneous evoked tail flick and hot plate nociceptive responsesas well as the chemical visceral elicited acetic acid writhing response were determined in rats following lumbar intrathecal administration of the dopamine (DA) agonist apomorphine. Apomorphine failed to influence tail flick latency even at high doses (660 nmol). In contrast, intrathecal apomorphine (33–330 nmol) produced a dose-dependent increase of the hot plate and acetic acid writhing responses, which was antagonized by the prior intrathecal administration of cis-flupenthixol (a DA receptor antagonist). Intrathecal pretreatment with either trans-flupenthixol (the inactive stereoisomer of cis-flupenthixol) methysergide, phentolamine or naloxone did not antagonize the apomorphine-induced increase of hot plate response latency. Intrathecal apomorphine did produce an increase of tail flick latency following pretreatment with methysergide and phentolamine, however. Intraventricular administration of apomorphine (82.5–165 nmol) had no influence on either tail flick or hot plate response latencies. The present data provide evidence for the modulatory role of apomorphine on spinal afferent sensory functions. It is suggested that a spinal DA receptor population has an inhibitory effect on noxious input to the spinal cord.

Immobilization-induced analgesia: Possible involvement of a non-opioid circulating substance

Stress induced analgesia (SIA) and stress-induced changes in body temperature were studied in mice and rats. Immobilization was used as the stressor. Nociception was measured with the tail-flick method and body temperature was recorded in the colon. Within 5 min of immobilization a similar increase in tail-flick latencies was observed in the two species. Concomitantly, the body temperature increased in the rats and decreased in the mice. Transection of the spinal cord 7 days before the experiments tended to increase the effect of stress on the tail-flick latencies in both species. Pretreatment with naloxone HCL (2 mg/kg SC, 5 min before immobilization) did not influence SIA in either intact or spinal rats. Thus, analgesia induced by immobilization may be due to a non-opioid substance acting peripherally or reaching the spinal cord via the systemic circulation.

D-baclofen: Is it an antagonist at baclofen receptors?

1. Following intrathecal administration Into the spinal subarachnoid space, baclofen produced dose related increases in tail flick latency. L-Baclofen was twice as potent as the DL-racemate and 100 times more potent than D-baclofeu. 2. When D-baclofen was injected intrathecally 15 min prior to L-baclofen, the subsequent effect of L-baclofen was markedly reduced. This reduction was dose-related for D-baclofen in doses at least 20 times the L-baclofen dose. D-baclofen administered concomitantly with L-baclofen only slightly increased the effect of L-baclofen. 3. Pretreatment with D-baclofen (up to 10 times the dose of L-baclofen) did not inhibit the effect of L-baclofen when drugs were injected intraperitoneally. 4. These results indicate that D-baclofen can antagonize the antinociceptive effect of L-baclofen following intrathecal administration. D-Baclofen should prove to be a useful tool for investigation of the role of stereoselectlve baclofen receptors in a variety of pharmacological processes.

Antinociceptive effect of centrally administered cimetidine and dimaprit in the rat.

Cimetidine, an H2 receptor antagonist, administered into a lateral ventricle of the rat brain caused a significant increase in tail flick latency. Dimaprit, a specific H2 agonist, failed to counteract the analgesic effect of cimetidine. In contrast, it enhanced the effect of cimetidine and per se had marked analgesic activity. The specific opioid antagonist naloxone was without effect. Pretreatment with CaCl2 completely prevented the action of cimetidine. These findings suggest that the analgesic action of cimetidine and dimaprit is not due to specific effects on H2 receptors.

Serotonin receptor antagonists induce hyperalgesia without preventing morphine antinociception

5-Hydroxytryptamine (5-HT) receptor blockade by administration of mianserin (1 mg/kg) or metergoline (0.25 mg/kg) shortened the response latencies of rats in the hot-plate (hind-paw lick response) and tail-flick tests, but did not consistently attenuate the antinociceptive effect of morphine (1.25–5.0 mg/kg). Injection of the opiate receptor antagonist naloxone (1 mg/kg) did not change tail-flick response latencies and did not interfere with the antinociceptive action of the 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). The antinociceptive effect of morphine was reduced in chronically spinal rats, although significant increases in tail-flick latencies were observed after 2.5 and 5.0 mg/kg. Concomitant administration of 5-MeODMT failed to restore the effect of morphine in spinal rats. In the hot-plate test, morphine did not reliably prolong latencies to forepaw lick, indicating that this response is not a useful measure of pain sensitivity. The results suggest that different mechanisms underlie the analgesia induced by systemic administration of morphine and 5-HT mediated tonic inhibition of nociception.

Partial cross tolerance to D-Ala 2-D-Leu 5-enkephalin after chronic spinal morphine infusion

The development of tolerance to morphine and cross tolerance to D-Ala 2-D-Leu 5-enkephalin (DADL) at spinal cord level to the inhibition of tail flick response was studied in rats tolerant to morphine. The long term intrathecal infusion of morphine sulfate was accomplished by means of an osmotic minipump. Intrathecal infusion of morphine sulfate (2 μg/hr) markedly elevated the tail flick latency measured 24 hr after the start of infusion. The increased tail flick latencies gradually decreased during 6 days of intrathecal infusion of morphine sulfate. Tolerance to morphine and DADL was determined by inhibition to the tail flick response after intrathecal administration of cumulative doses of morphine sulfate and DADL. Chronic intrathecal infusion of morphine induced a marked tolerance to morphine but developed only a slight cross tolerance to DADL. The results indicate that there exists two separate types of opioid receptor, μ- and δ-opioid receptor in the spinal cord of rats.

Mixed opioid/nonopioid effects of dynorphin and dynorphin related peptides after their intrathecal injection in rats

Dynorphin dose-dependently increased the tail flick latency of rats to radiant heat following its intrathecal injection. This effect was accompanied by an alteration in motor function that was characterized by a flaccid extension of the hindlimbs and flaccidity of the tail. Naloxone (10 but not 1 mg/kg) blocked the antinociceptive effect and motor disturbance produced by dynorphin. The non-opioid analogue des-Tyr 1-dynorphin (1–13) also increased tail flick latency and produced paralysis. Dynorphin (1–8) significantly elevated tail flick latency without affecting motor function. Furthermore, the effect of dynorphin (1–8) was blocked by 1 mg/kg naloxone. These data suggest a possible physiological role of dynorphin in influencing motor function in the spinal cord and a role of dynorphin (1–8) in modulating pain transmission. Another finding of the present study was that dynorphin was approximately ten times more potent in producing its effects when injected one day after surgery compared to when it when it was injected one week or more after surgery.

Effects of intrathecal ACTH on opiate A algesia in the rat

The effects of administration of opiates and ACTH onto the lumbar spinal cord of rats were investigated. ACTH, morphine and β-endorphin were administered to the lumbar spinal cord via chronically implanted spinal catheters. Effects on nociceptive thresholds using the tail-flick test were observed. Intrathecal morphine and β-endorphin caused analgesia whereas effects of intrathecal ACTH were variable. About half the animals showed small increases in tail-flick latency with intrathecal ACTH, the other half showing either decreases in tail-flick latency or no effect. In contrast, intrathecal ACTH consistently reversed the analgesia caused by either intrathecal morphine or β-endorphin. The results are discussed in terms of interactions between ACTH and opiates.

Effect of emotions on nociceptive threshold in rats

Tail-flick latency was measured in male rats exposed to inescapable footshock for 2 min (0.8 mA, 1 sec every 5 sec), in rats that witnessed effects of footshock on other rats and in rats exposed to a strong auditory stimulus (8 kHz, 96 db SPL) either intermittently (1 sec every 5 sec) or continuously for 2 min. A significant increase in tail-flick latency occurred in rats exposed to footshock as well as in rats that only witnessed footshock. Continuous auditory stimulation also had an analgesic effect, while intermittent stimulation similar to the sound produced by rats given footshock failed to affect tail-flick latency significantly. The analgesic effect of witnessing footshock habituated rapidly and was counteracted by naloxone (10 mg/kg IP), while naloxone failed to affect audiogenic analgesia. Analgesia produced by witnessing a noxious treatment is probably mediated by an emotional reaction. It is suggested that the phenomenon be termed “emotiogenic analgesia.”

Dopaminergic effects on tail-flick response in spinal rats

R-Apomorphine (0.02–1.75 μmol/kg), administered by intrathecal infusion to spinalized rats, caused a dose-dependent increase in tail-flick latency. The effect of R-apomorphine was counteracted significantly by the dopaminergic receptor antagonists cis-flupenthixol (0.20–3.94 μmol/kg) and (+)-butaclamol (0.78 μmol/kg), but not by their enantiomers nor by phenoxybenzamine (29.40 μmol/kg) or methysergide (28.40 μmol/kg). The findings suggest that dopaminergic mechanisms play a role in the modulation of nociception in the spinal cord.

Tail pinch behavior and analgesia in diabetic mice

Mild tail pinch induced “consummatory” behaviors in mice. The major tail pinch behavior appeared to be chewing with food ingestion occurring possibly as an epiphenomenon. All tail pinch behaviors were obliterated by the dopamine antagonist haloperidol; and the opiate antagonist, naltrexone, decreased eating without altering chewing. The combination of dopamine blockade and tail pinch induced jumping behavior in mice. Diabetic mice showed increased tail flick latencies to radiant heat and to the induction of tail pinch behaviors, displaying these behaviors less commonly than their homozygote and heterozygote littermate controls.

The correlation between swim-stress induced antinociception and [ 3H] leu-enkephalin binding to brain homogenates in mice

Mice which had been made to swim for 3 minutes showed a tail flick latency which was significantly longer than that of unswum controls. The [ 3H] leu-enkephalin [LE] binding to brain homogenates from swum mice was significantly reduced when compared with that from unswum controls. Scatchard analysis revealed that the reduction in binding occurred at the LE low affinity site. However, when homogenates were allowed a preincubation period of 20 min at 37°C, the difference in LE binding between swum and unswum mice was no longer apparent. These data are interpreted to suggest that the reduced LE binding may be due to the occupation of a proportion of the opiate receptor population by an endogenous ligand. A correlation between the duration of the swim induced antinociceptive response and the changes in LE binding is described which although non-significant, is consistent with the interpretation for the involvement of endogenous opiates in the observed increases in tail flick latency.

Increased GABA binding in mouse brain following acute swim stress

Acute swim stress of mice produces increases in the density of high and low affinity binding sites in the brain for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), together with analgesia as measured by an increase in tail flick latency. Apparent tolerance develops an repeated swimming with analgesia and GABA binding returning towards control levels. The time course of analgesia and Increases in GABA binding following a single swim are also similar. Acute swim stress does not alter diazepam binding. GABA systems may be important in analgesia and in responses to environmental stress.

Stress-induced release of brain and pituitary β-endorphin: Major role of endorphins in generation of hyperthermia, not analgesia

The present paper examines the conjectured causal relationship between the alterations in brain, pituitary and plasma levels of endorphins and the antinociception (analgesia) and hyptermia elicited by acute stress. A 5-min foot-shock instigated a significant depression in the levels of β-endorphin immunoreactivity (β-EI) in both the hypothalamus and periventricular β-endorphinergic fibre-containing tissue. A large elevation in plasma levels of β-EI, consisting of about 70% β-endorphin (β-EP), and 30% β-lipotropin (β-LPH) was associated with a significant reduction in the β-EI content of both the anterior (AL) and neurointermediate (NIL) lobes of the pituitary. No concomitant changes in the levels of Met-enkephalin immunoreactivity (M-EI) in discrete areas of brain and pituitary were detectable. Application of high (10 mg/kg) but not a low (1 mg/kg) dose of naloxone, prior to foot-shock, slightly reduced the increase in tail-flick latency evoked by this stress. In contrast, both of these doses strongly and dose-dependently attenuated the accompanying rise in core temperature (Tc). Chronic (∼30 day) morphine treatment resulted in a 45% decrease in the NIL content of β-EI and a clear depression in its basal plasma levels, although a substantial post-stress rise in plasma β-EI was still found: stress-induced analgesia (SIA) was enhanced, but the concurrent stress-induced hyperthermia (SIH), reduced in morphinized animals. These data demonstrate that stress produces a generalized mobilization of both central and pituitary pools of β-EI, and indicate that endorphins may play a more important role in the mediation of changes in Tc than in the generation of the concomitant increase in nociceptive threshold, upon activation by stress.

Lesions of the hypothalamic arcuate nucleus produce a temporary hyperalgesia and attenuate stress-evoked analgesia

In an attempt to elucidate the role of β-endorphin in the modulation of ‘basal’ nociceptive threshold and in the mediation of the antinociception (analgesia) evoked by stress, a series of lesions of the arcuate nucleus, the origin of the central system of β-endorphinergic neurones, were performed. These lesions produced an ∼80% depression in the level of β-endorphin immunoreactivity in both the hypothalamus and periventricular β-endorphinergic fibre-containing tissue. A 50% decrease in the neurointermediate lobe content of immunoreactivity, but no change in the levels of this in the anterior lobe was also observed. Arcuate lesioned rats were significantly hyperalgesic in comparison to sham animals on day 4 post-operation, but on days 10 and 12, the basal nociceptive threshold of lesioned and sham groups did not differ significantly. On day 12 post-surgery upon exposure to 5 min foot-shock stress, lesioned rats developed a significantly smaller increase in tail-flick latency than did sham animals. These data are evidential of the importance of the arcuate nucleus in the determination of basal nociceptive threshold and in the generation of the analgesia which accompanies stress and are, further, suggestive of a role of central β-endorphin in the mediation of these processes.

The antinociceptive effects of GABA agonists and antagonists in mice

Changes in GABA-associated systems in brain and spinal cord have been implicated in morphine (MO) activity. The antinociceptive activity of the GABA agonists, muscimol (MUS) and aminooxyacetic acid (AOAA) and the GABA antagonists picrotoxin (PIC) and bicuculline (BIC) were investigated in the phenylquinone-induced abdominal constriction (PQ) and tail flick (TF) procedures. In PQ after SC administration, PIC and MUS were slightly less active than MO ( ED 50=0.29 mg/ kg) while PIC and AOAA were 3 and 15 times less potent respectively. The activity of AOAA ( ED 50=4.2 mg/ kg) was increased 5-fold after pretreatment with naloxone. Using subconvulsant doses, maximal increases in TF latencies ranged from 0.39 sec for MUS to 1.31 sec for PIC. Significant changes in TF latency between sham and spinally-transected mice was found only for picrotoxin (2.5 mg/kg). Although GABA systems are involved in the perception of various nociceptive stimuli no distinction in activity could be made between agonists and antagonists.

Responses of monkey thalamus to somatic stimuli under chloralose anaesthesia

During a previous study of the nucleus parafascicularis (Pf), cells were recorded in the lateral habenula (HbL) which exhibited response patterns to peripheral noxious stimuli similar to those recorded in the Pf. In order to study the possible role of the habenular complex (Hb) in pain processing, we investigated the effect of electrical stimulation of the Hb on the tail-flick latency. For each series of experiments, the Hb of 15 female rats was implanted unilaterally, with bipolar electrodes, on either the right or left side. A week later, the animals were submitted to measurements of tail-flick latency, every 10 min, for a period of 3 h. The amount of analgesia was estimated by the percentage increase in latency. Five intensities of current (50, 100, 200, 300 and 400 μA) were used for stimulation during 60 s, at 50 Hz and 0.5-ms pulse width. A group of animals were given naloxone i.p. (1 mg/kg) 40 min after Hb stimulation at 200 μA to study the reversibility of the analgesia. A second group had their Hb destroyed by coagulation and the effect on tail-flick latency was checked once a week for 4 weeks. The results of these experiments clearly demonstrate Hb stimulation-induced analgesia, the maximum of which occurs 60–80 min after stimulation and then decreases slowly. The maximal amount of analgesia increases with the intensity of current up to 200 μA, without any behavioral side effects. At 300 μA, the analgesia is not significantly different from the one induced at 200 μA. However at 400 μA, behavioral side effects (fear, escape) appear and the analgesia is weaker. Two-hundred μA appears to be the most efficient current intensity and induces an average of 80% increase in tail-flick latency. The group which was given naloxone exhibited a dramatic and complete reversal of analgesia. The group which had their Hb destroyed did not show any difference from the control group a week after surgery. During the following weeks, both lesioned animals and controls exhibited a habituation-like analgesia, without any significant difference (the index of analgesia was 45.73 ± 23.65% for the lesioned rats and 51.82 ± 29.18% for the controls), which was not naloxone reversible. A review of the literature does not provide an explanation for Hb-induced analgesia. The medial habenula which projects mainly on the interpeduncular nucleus has a very high content in pain-related transmitters such as substance P and enkephalins. The HbL projects on the nucleus raphe dorsalis, which is, within the periaqueductal gray matter, the essential site from which analgesia can be obtained by electrical stimulation36,37. This provides a hypothesis for the mechanism of action which must be investigated by further experiments.