Significant Increase In Tail Flick Latency Research Articles

Study the antinociceptive effect of intracerebroventricular injection of aqueous extract of origanum vulgare leaves in rat: possible involvement of opioid system.

The aim of study was to investigate the antinociceptive effect of intracerebroventricular (ICV) microinjection of Origanum vulgare (ORG) extract and possible involvement of opioid receptors. Cannula was inserted into left ventricle of male rats. Five days after surgery Tail Flick Latency (TFL) was measured after ICV microinjection of, ORG (1, 3 and 6 µg / rat). Effective dose of ORG was injected ICV in concomitant with morphine (2 mg/kg, IP), naloxone (2 mg / kg, IP) and saline (0.5 µl/rat) and TFL was recorded. The co- administrationof ORG extract with morphine showed a significant increase in TFL and naloxone, pretreatment significantly inhibited the antinociceptive activity of ORG and morphine. The aqueous extract of ORG possesses antinociceptive activities in the tail-flick test in a dose dependent manner. ORG - induced antinociception may have been mediated by opioid systems.

Dopamine Release is Involved in Antinociceptive Effect of Theophylline

ABSTRACTThe methylxanthines, e.g., theophylline, are widely used for the treatment of bronchial asthma. Additionally, a pain relieving effect of theophylline has been reported in patients as well as in experimental animals. The mechanism of this antinociceptive action is not clear. In this study, involvement of dopaminergic system in theophylline-induced antinociception was evaluated using tail flick test model. Swiss albino mice, (either sex, weighing 25–30 g) with base line tail flick latencies (TFL) between 2.0 and 3.5 s, were used. TFL was recorded before and at intervals of 15, 30, 45, and 60 min. after drug treatment. The experimental protocol was duly approved by the Institutional Animal Ethics Committee, All India Institute of Medical Sciences, New Delhi, India. To determine the role of dopaminergic system, the mice were pretreated with either D1 or D2 dopaminergic receptor antagonists SCH 23390 and haloperidol, respectively, prior to treatment with theophylline. Another group of animals received apomorphine along with theophylline. The dose of theophylline used, i.e., 10 mg/kg, intraperitoneally (i.p.), had shown a significant increase in TFLs. The theophylline-induced antinociception, 10 mg/kg, i.p., was reversed by pretreatment with both D1 and D2 dopaminergic receptor antagonists SCH 23390 and haloperidol as well as with apomorphine (1 mg/kg) pretreatment. The results suggest that theophylline-induced antinociception is due to release of dopamine.

Two histamine H2 receptor antagonists, zolantidine and cimetidine, modulate nociception in cholestatic rats

Cholestasis is associated with analgesia. The histamine H(2) receptors control pain perception. The involvement of histamine H(2) receptors on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using zolantidine and cimetidine as two H(2) receptor antagonists and dimaprit as a selective H(2) receptor agonist. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct at the midpoint between them. A significant increase in tail-flick latencies was observed in cholestatic rats compared to non-cholestatic rats. Administration of zolantidine (10, 20 and 40 mg/kg) and cimetidine (25, 50 and 100 mg/kg) in the cholestatic group significantly increased tail-flick latencies while dimaprit (10 and 20 mg/kg) injection in the cholestatic group decreased tail-flick latencies compared to the saline treated cholestatic group. Antinociception produced by injection of zolantidine and cimetidine in cholestatic rats was attenuated by co-administration of naloxone. Drug injection in non-cholestatic rats did not alter tail-flick latencies compared to the saline treated rats at any of the doses. At the doses used here, none of the drugs impaired motor coordination as revealed by the rota rod test. These data show that the histamine H(2) receptor system may be involved in the regulation of nociception during cholestasis. According to the hypothesis that increasing the nociception threshold in cholestasis may lead to a decrease in the perception of pruritus, the provision of the drugs that increase the threshold to nociception may be a novel approach to the treatment of cholestatic pruritus.

Estrogen-dependent, sex-specific modulation of mustard oil-induced secondary thermal hyperalgesia by orphanin FQ in the rat

Activation of opioid receptor-like 1 receptor (ORL 1) by intrathecal administration of orphanin FQ (OFQ), an endogenous ligand for the ORL 1 receptor, has been shown to produce antinociception. In addition, we have recently shown gonadal hormone-dependent, sex-specific modulation of acute spinal nociception such that estrogen attenuated OFQ-induced antinociception in the female whereas testosterone was required for the expression of antinociception in the male. However, sex-related differences in the role of OFQ under hyperalgesic conditions are unknown. Hence, we investigated whether OFQ produces sex-specific modulation of mustard oil-induced secondary thermal hyperalgesia in the rat. Mustard oil application to the hind limb significantly reduced the tail-flick latencies (TFL) in male, and ovariectomized (OVX), estradiol treated ovariectomized (OVX + E), proestrous (ProE) and diestrous (DiE) females. Intrathecal administration of OFQ not only attenuated mustard oil-induced decrease in TFLs, i.e. reversed hyperalgesia, but also led to a significant increase in TFLs above the baseline, i.e. produced antinociception in male, OVX, and diestrous rats. However, OFQ failed to alter TFLs in proestrous or OVX + E females, thus these two groups with elevated estrogen levels remained hyperalgesic following mustard oil treatment. These findings demonstrate that OFQ modulates mustard oil-induced secondary hyperalgesia in an estrogen-dependent, sex-specific manner.

Epidural Lidocaine Induces Dose-Dependent Neurologic Injury in Rats

Although epidural lidocaine administered as a bolus has been shown to cause little neurotoxicity, local anesthetics are often administered repetitively or continuously into the epidural space, and in high doses may induce neurologic injury. We investigated whether epidural lidocaine is neurotoxic when a large dose is continuously administered in rats, and whether the functional impairment and histologic damage is dose dependent. In Experiment 1, 13 rats received a 120-min epidural infusion (at 5 microL/min) of saline or 2% lidocaine. Four days after infusion, rats given 2% lidocaine developed significantly more prolonged tail-flick latencies and showed more apparent morphologic damage than those given saline. In Experiment 2, 41 rats were randomly divided into 5 groups to receive an epidural infusion of saline for 120 min or 5% lidocaine for 15, 30, 60, or 120 min at a rate of 5 muL/min. Rats given 5% lidocaine for 120 min developed a significant increase in tail-flick latency. Paw pressure thresholds did not change in any group. Nerve injury scores for rats given 5% lidocaine for 30, 60, and 120 min were significantly higher than those for rats given saline. Significant difference in damage in nerve roots was also observed among rats given the anesthetic for different durations of time; nerve injury scores with 120-min infusion were higher than with 15- and 30-min infusions, and injury with 60-min infusion was greater than with 15-min infusion. In conclusion, these results suggest that epidural lidocaine causes dose-dependent neurotoxicity after continuous infusion in rats.

The analgesic effect of Carum copticum extract and morphine on phasic pain in mice

Pain is a universal complaint, which needs further investigations for new pain relieving agents. Carum copticum (L.) Sprague ex Turrill is a plant in Umbelliferae family, which is mentioned to have some therapeutic effects on headache and joint pains in Iranian traditional literature, but there are not enough scientific reports to prove its effects on pain. So, we conducted to design an experimental clinical trial study to assess and compare the analgesic effect of ethanolic extract of Carum copticum fruit with morphine by using a tail-flick analgesiometer device. Our results indicate that the test drug produced significant increase in tail-flick latency (TFL) during 2 h post-drug administration ( p < 0.05). The peak of the effect was observed at 45 min after drug injection, which was comparable to that of 1 mg/kg morphine (i.p.). Positive results in this type of analgesiometric test indicate that the antinociceptive action may be of the opoid type. The present study supports the claims of Iranian traditional medicine showing that Carum copticum extract possesses a clear-cut analgesic effect. However, further investigations are required to evaluate the efficacy and safety of this herbal medication in man.

Effect of the antidepressant nefazodone on the density of cells expressing mu-opioid receptors in discrete brain areas processing sensory and affective dimensions of pain.

The principal use of antidepressants is in the treatment of depression and affective disorders. Antidepressants have also been used as an adjuvant to analgesics in pain treatment. However, in chronic treatment, their antinociceptive and antidepressive effects coexist simultaneously. Antidepressants can interact with the opioid system, which is also involved in regulating nociceptive processing and affective state. Chronic antidepressants could act by increasing mu-opioid receptor expression in many brain areas involved in the regulation of nociception and affective state. The aim of this study was to evaluate the antinociceptive and antidepressant-like effects and the possible variations in mu-opioid receptor expression induced by a chronic nefazodone treatment in brain areas related to pain and affective state. Wistar rats were chronically treated with nefazodone (10 and 25 mg/kg IP, twice a day, for 14 days). Twelve hours after the last day 14 dose of nefazodone, a tail-flick test was performed. After the administration of a daily dose of nefazodone, Porsolt's test was carried out 12 h after last dose. Two hours after completion of 14 days treatment, other animals were processed for mu-opioid receptor immunocytochemistry using polyclonal antisera raised in rabbits. Several brain regions were analyzed: the frontal and cingulate cortex, the dorsal raphe nucleus and the periaqueductal gray. Chronic nefazodone treatment induced a significant increase in tail-flick latency and a significant decrease in immobility time at total doses of 20 and 50 mg/kg per day ( P<0.05). In treated animals, the density of neural cells immunostained for mu-opioid receptor in the frontal and cingulate cortices, dorsal raphe nucleus and periaqueductal gray had increased after chronic nefazodone compared to controls. Therefore, chronic nefazodone induces antinociceptive and antidepressant-like effects in rats and increases mu-opioid receptor expression in brain areas related to pain and affective state. These results suggest that antidepressants could be effective on somatic and affective dimensions of pain and this action could be related to its influence on the opioid system.

Potentiation of morphine analgesia by BQ123, an endothelin antagonist

Several neurotransmitter mechanisms have been proposed to play a role in the actions of morphine. The present study is the first to provide evidence that central endothelin (ET) mechanisms are involved in the modulation of pharmacological actions of morphine. The effect of intracerebroventricular (i.c.v.) administration of endothelin-A (ET A) antagonist, BQ123, on morphine-induced analgesia, hyperthermia, and catalepsy was determined in the rat. Morphine produced a significant increase in tail-flick latency as compared to control group. Pretreatment with BQ123 significantly potentiated the effect and duration of morphine (2 and 8 mg/kg, s.c.)-induced analgesia as compared to vehicle-pretreated control rats. The hyperthermic effect of morphine was not only significantly greater in BQ123-pretreated rats but also lasted for more than 6 h. ET antagonist, BQ123, did not affect the pharmacological effect of morphine on cataleptic behavior. These studies demonstrate that BQ123, a specific ET A receptor antagonist, significantly potentiated morphine-induced analgesia and hyperthermia in rats without affecting morphine-induced cataleptic behavior. [ 3 H ]-Naloxone binding was carried out to determine the possibility of BQ123 acting on opiate receptors. It was found that morphine could displace [ 3 H ]-naloxone but BQ123 did not affect [ 3 H ]-naloxone binding even at 1000 nM concentration. Therefore, it can be concluded that BQ123 does not act on opioid receptors. This is the first report suggesting that an ET A antagonist, BQ123, significantly potentiates the analgesic effect of morphine, possibly through a nonopioid mechanism.

Antinociceptive effects of carbachol microinjected into different portions of the mesencephalic periaqueductal gray matter of the rat

The changes in tail-flick latency (TFL) to noxious heating of the skin produced by the microinjection of carbachol (CCh) into the dorsal (dPAG), lateral (IPAG), and ventral (vPAG) portions of the mesencephalic periaqueductal gray matter (PAG) were studied in the rat. A significant increase in TFL was produced by CCh (0.2 μg/0.5 μl) microinjected into sites widely distributed within the PAG. The effect of CCh was stronger in the most caudal portion of the DPAG. Smaller effects were obtained after injection of CCh into the aqueduct, indicating that drug diffusion from theinjection sites to the aqueduct lumen is unlikely to cause the antinociceptive effect of CCh. Dimethyl-phenyl-piperazinium (0.35 μg/0.5 μl), but not bethanechol (0.22 and 0.44 μg/0.5 μl), produced effects similar to CCh (0.2 μg/0.5 μl), when injected into the dPAG. The effects of CCh were inhibited by the previous administration of mecamylamine (1 μg/0.5 μl), but not atropine (1 μg/0.5 μl) or naloxone (1 μg/0.5 μl), into the dPAG. These results are indicative that antinociception produced by CCh from the dPAG depends on nicotinic, but not muscarinic or opioid mechanisms within the dPAG. The intraperitoneal administration of phenoxybenzamine (1 mg/kg) or mecamylamine (1 mg/kg), but not naloxone (1 mg/kg), methysergide (1 mg/kg), or atropine (1 mg/kg), inhibited the effects of CCh injected into the dPAG. In contrast, a higher dose of intraperitoneal phenoxybenzamine (5 mg/kg) was ineffective against the antinociception evoked by CCh when injected into the vPAG. Therefore, the effects of CCh from the dPAG may depend on the activation of centrifugal pathways involving both nicotinic and α-adrenergic mechanisms. In addition, the results indicate that different cholinergic substrates in the PAG may mediate both α-adrenergic and non-α-adrenergic descending pain mechanisms activated by the dPAG and vPAG, respectively.

GABAergic modulation of nociceptive threshold: effects of THIP and bicuculline microinjected in the ventral medulla of the rat

Neurons of the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (NGCpα) have been implicated in the regulation of nociceptive threshold and production of antinociception. Previous studies have shown that the activity of these neurons is modulated by noradrenergic, cholinergic and serotonergic afferents. The present study examined whether these neurons are additionally subject to regulation by a GABAergic input. Microinjection of the GABA A receptor agonist 4 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 0.3 or 1.0 μg) in the NRM or NGCpα significantly decreased tail flick latency (TFL) and increased responsiveness to noxious pinch. Hot plate latency (HPL) was not affected by microinjection of 0.3 μg THIP. Although HPL was increased after microinjection of 1.0 μg THIP, this effect may reflect motoric disturbances. In contrast to the hyperalgesia produced by THIP, microinjection of the GABA A receptor antagonist bicuculline methiodide (0.04 or 0.1 μg) produced a small, but significant increase in TFL. Responsiveness to noxious pinch and HPL were not affected by either dose. These findings indicate that neurons of the NRM or NGCpα involved in the regulation of nociceptive threshold are subject to an inhibitory GABAergic input mediated by a GABA A receptor. However, in contrast to previously described inhibitory inputs, the GABAergic influence does not appear to be tonically active to a substantial extent in the unanesthetized rat.

Stressors produce a concurrent decrease and increase in reflex amplitude in rats treated with naloxone

The effect of inescapable foot-shock on the tail-flick response and on the startle response to brief shocks and brief tones was studied in rats. In the first experiment, 25 minutes of inescapable foot shock (stressor) produced a significant increase in tail-flick latency which was antagonized by the opioid antagonist naloxone (2.0 mg/kg). In the second experiment, the startle response to an electric shock to the tail was significantly diminished by the stressor, and this effect was not significantly reduced by naloxone. However, the size of the startle response to a brief tone was significantly increased in rats treated with naloxone. Thus, rats injected with naloxone had a decreased startle to shock but an increased startle to tone following inescapable foot shock. Finally, tones which preceded shocks by one second produced a facilitation of the startle response to the shocks in tests that followed exposure to the stressor. This facilitation was not affected significantly by naloxone. These results indicate that the changes in the startle response following the stressor were not mediated exclusively by endogenous opioids.

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.”