Increase In Tail-flick Latency Research Articles

Possible involvement of the spinal nitric oxide/cGMP pathway in vincristine-induced painful neuropathy in mice

The mechanisms that underlie the development of vincristine-induced painful neuropathy are poorly understood. The nitric oxide (NO)-cGMP pathway has been reported to be involved in the spinal transmission of nociceptive information. In the present study, we examined whether alterations in spinal nociceptive processing via the NO-cGMP pathway contribute to vincristine-induced painful neuropathy in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg 1 day after the measurement of pre-drug latency in the tail-flick test, and then treated with a dose of 0.125 mg/kg twice a week for 6 weeks. In vincristine-treated mice, a significant decrease in tail-flick latencies developed at 4 weeks after treatment. Pretreatment with l-arginine (30–300 mg/kg, s.c.), a substrate of NO synthase (NOS), dose-dependently increased the tail-flick latencies in vincristine-treated mice. The l-arginine-induced increase in tail-flick latencies in vincristine-treated mice was completely reversed by i.t. pretreatment with N G-nitro- l-arginine methyl ester ( l-NAME, 3–30 nmol), a NOS inhibitor. Furthermore, i.t. pretreatment with 8-bromoguanosine 3′, 5′-cyclic monophosphate (8-Br-cGMP, 0.3–3.0 nmol), a membrane-permeable cGMP analog, dose-dependently increased the tail-flick latencies in vincristine-treated mice. The contents of NO metabolites, cGMP and protein levels of neuronal NOS in the spinal cord in vincristine-treated mice were significantly reduced compared to those in vehicle-treated naive mice. These results indicate that dysfunction of the l-arginine/NO/cGMP cascade in the spinal cord may trigger vincristine-induced thermal hyperalgesia in mice.

Effect of leukemia inhibitory factor in experimental cisplatin neuropathy in mice

In this study, the effect of leukemia inhibitory factor (LIF) on cisplatin (CDDP)-induced neuropathy was evaluated. Mice were treated with CDDP, 2 mg/kg i.p. twice a week nine times. During the last week some of the mice were also injected with LIF, 2 μg/kg s.c. every other day for a total of four injections. Development of neuropathy was evaluated with changes in tail flick latency and sensory nerve conduction velocity (NCV). At the end of the treatment period dorsal root ganglia (DRG) were microscopically examined. Some of the DRGs were explanted into extracellular matrix, covered with culture medium and incubated for 3 days. During and at the end of the incubation, cellular migration and axonal outgrowth from the DRGs were quantified. LIF proved effective in reversing the increase in tail flick latency ( p < 0.05 ) and improving the reduction in NCV induced by CDDP. CDDP led to smaller nuclear and somatic size in neurons, while with LIF, the latter was restored to control values ( p < 0.01 ). No apoptotic nucleus was observed among DRG neurons while very few and moderate numbers detected among satellite and Schwann cells, respectively. With LIF, none of the cells had apoptosis. CDDP caused a decrease in the number of migrating cells and in the length of outgrowing axons while LIF treatment restored both capacities ( p < 0.05 ) In conclusion, in CDDP-induced neuropathy, LIF was found to be effective in correcting some functional and morphological deteriorations related with major involvement of Schwann cells.

Role of muscarinic and nicotinic cholinergic receptors in an experimental model of epilepsy-induced analgesia

The blockade of GABA-mediated Cl − influx with pentylenetetrazol (PTZ) was used in the present work to induce seizures in animals. The neurotransmission in the postictal period has been the focus of many studies, and there is evidence suggesting antinociceptive mechanisms following tonic–clonic seizures in both animals and men. The aim of this work was to study the involvement of acetylcholine in the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). Analgesia was measured by the tail-flick test in eight albino Wistar rats per group. Convulsions were followed by significant increases in tail-flick latencies (TFLs) at least for 120 min of the postictal period. Peripheral administration of atropine (0.25, 1 and 4 mg/kg) caused a significant dose-dependent decrease in the TFL in seizing animals, as compared to controls. These data were corroborated by peripheral administration of mecamylamine, a nicotinic cholinergic receptor blocker, at the same doses (0.25, 1 and 4 mg/kg) used for the muscarinic cholinergic receptor antagonist. The recruitment of the muscarinic receptor was made 10 min postconvulsions and in subsequent periods of postictal analgesia, whereas the involvement of the nicotinic cholinergic receptor was implicated only after 30 min postseizures. The cholinergic antagonists caused a minimal reduction in body temperature, but did not impair baseline TFL, spontaneous exploration or motor coordination in the rotarod test at the maximal dose of 4 mg/kg. These results indicate that acetylcholine may be involved as a neurotransmitter in postictal analgesia.

Diverse effects of intrathecal pituitary adenylate cyclase-activating polypeptide on nociceptive transmission in mice spinal cord

Pituitary adenylate cyclase-activating polypeptide (PACAP) immunoreactive neural elements have been detected in the mouse spinal cord. The discrepancy of PACAP actions in the role of sensory transmission has been proposed to have potentiation and inhibition on nociceptive responses after intrathecal application of PACAP. The aim of the present study was to assess nociceptive transmission of PACAP in the mouse spinal cord by comparison with that of substance P (SP). The intrathecal injection of PACAP induced licking or scratching behavior similar to that of SP. These PACAP-induced aversive behaviors showed different manner from SP-induced responses in point of time course. SP-induced aversive responses quickly increased and suddenly disappeared almost within 1 min. Meanwhile, following a long latency after the injection, PACAP-induced aversive responses gradually appeared, and then persisted more than 60 min. In the early phase, PACAP produced an increase of tail flick latency. Pretreatment with 6-hydroxydopamine (6-OHDA) which destroys noradrenaline neuron of descending pain inhibitory systems in the spinal cord markedly abridged the latency and augmented the duration of PACAP-induced aversive responses. In this way, PACAP exhibits diverse effects on nociception, such as an analgesic role in early phase of the injection and subsequently lasting algesia. These results suggest that PACAP as a neurotransmitter or neuromodulator might have crucial role in nociceptive transmission system.

Presynaptic inhibition and spinal pain processing in mice: a possible role of the NKCC1 cation-chloride co-transporter in hyperalgesia*1

We have examined the role of the NKCC1 sodium-potassium-chloride-cotransporter in the generation of touch-evoked pain. The pain behavior of NKCC1 knockout mice (KO) was studied and compared to that of heterozygous (HE) and wild-type (WT) littermates. NKCC1 KO mice showed an increase in tail flick latencies and a reduction of the duration of pain behavior induced by intradermal capsaicin compared to HE and WT mice. All three groups of animals expressed a normal level of plasma extravasation following capsaicin applications. NKCC1 KO mice showed a reduction in stroking hyperalgesia (touch-evoked pain) compared to WT and HE mice but no differences were detected between the three groups in the expression of punctate hyperalgesia. As the NKCC1 co-transporter is responsible for the generation of presynaptic inhibition between afferent terminals in the spinal cord, these results support the notion that presynaptic interactions between low and high threshold afferents can underlie touch-evoked pain.

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.

Presynaptic inhibition and spinal pain processing in mice: a possible role of the NKCC1 cation-chloride co-transporter in hyperalgesia

We have examined the role of the NKCC1 sodium-potassium-chloride-cotransporter in the generation of touch-evoked pain. The pain behavior of NKCC1 knockout mice (KO) was studied and compared to that of heterozygous (HE) and wild-type (WT) littermates. NKCC1 KO mice showed an increase in tail flick latencies and a reduction of the duration of pain behavior induced by intradermal capsaicin compared to HE and WT mice. All three groups of animals expressed a normal level of plasma extravasation following capsaicin applications. NKCC1 KO mice showed a reduction in stroking hyperalgesia (touch-evoked pain) compared to WT and HE mice but no differences were detected between the three groups in the expression of punctate hyperalgesia. As the NKCC1 co-transporter is responsible for the generation of presynaptic inhibition between afferent terminals in the spinal cord, these results support the notion that presynaptic interactions between low and high threshold afferents can underlie touch-evoked pain.

Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist

Systemic administration of a cannabinoid agonist produces antinociception through the activation of pain modulating neurons in the rostral ventromedial medulla (RVM). The aim of the present study was to determine how a cannabinoid receptor agonist acting directly within the RVM affects neuronal activity to produce behaviorally measurable antinociception. In lightly anesthetized rats, two types of RVM neurons have been defined based on changes in tail flick-related activity. On-cells increase firing (on-cell burst), whereas off-cells cease firing (off-cell pause), just prior to a tail flick. The cannabinoid receptor agonist WIN55,212–2 was microinfused directly into the RVM while monitoring tail flick latencies and on- and off-cell activity. Microinfusion of WIN55,212–2 (2.0 μg/μl and 0.4 μg/μl) reduced the tail flick-related on-cell burst, decreased the duration of the off-cell pause, and increased off-cell ongoing activity. These changes were prevented by co-infusing the CB1 receptor antagonist, SR141716A (0.35 μg/μl), with WIN55,212–2 (0.4 μg/μl). Furthermore, 2.0 μg/μl WIN55,212–2 delayed the onset of the off-cell pause and increased tail flick latencies. Microinfusion of WIN55,212–2 to brain regions caudal or lateral to the RVM had no effect on RVM neuronal activity or tail flick latencies. These results indicate that cannabinoids act directly within the RVM to affect off-cell activity, providing one mechanism by which cannabinoids produce antinociception.

Taste modulation of nociception differently affects chronically stressed rats

Stress responses cover a wide range of physiological changes, including alterations in the perception of and response to pain. Animals submitted to repeated stress present altered nociception and this effect is part of this process of adaptation; in addition pleasant and unpleasant experiences with tastes and odors have been shown to affect distinct behavioral aspects, such as pain perception. The aim of the present study is to verify the responses of repeatedly stressed rats (1 h of daily immobilization during 40 days) to pleasant and unpleasant tastes on nociception, when compared to control animals. An increase in the tail-flick latency (TFL) was observed 5 min after exposure to a sweet taste in the control group, whereas no effect was observed in chronically stressed animals. When submitted to an unpleasant taste (5% acetic acid), the chronically stressed group presented an increase in TFL, whereas no effect was observed in the control group. In conclusion, chronically stressed animals present different nociceptive responses to sweet and acid tastes; although control animals suitably respond to a sweet stimulus, stressed animals seem to be more apt to react to the unpleasant stimulus.

Quercetin, a bioflavonoid, attenuates thermal hyperalgesia in a mouse model of diabetic neuropathic pain

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, has been recognised as one of the most difficult types of pain to treat. Lack of understanding of etiology involved, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve pain. The aim of the present study was to explore the antinociceptive effect of a bioflavonoid, quercetin, both in control and streptozotocin (STZ)-induced diabetic mice. After 4 weeks of a single intraperitoneal injection of STZ (200 mg/kg), both control and diabetic mice were subjected to test thermal hyperalgesia by tail-immersion assay (warm water). Diabetic mice exhibited a significant hyperalgesia as compared with control mice. Quercetin (100 but not 50 mg/kg po) produced a marked increase in tail-flick latencies in both diabetic and nondiabetic mice. Quercetin-induced increase in nociceptive threshold was reversed by naloxone (2 mg/kg ip), an opioid receptor antagonist. These preliminary results indicate an antinociceptive activity of quercetin, probably through modulation of opioidergic mechanism and point towards its potential to attenuate diabetic neuropathic pain.

Anti-nociception following exposure to trimethylthiazoline, peripheral or intra-amygdala estrogen and/or progesterone

Estradiol (E 2) and/or progesterone (P) to the amygdala may influence stress-induced analgesia following predator odor, trimethylthiazoline (TMT), exposure. Ovariectomized (ovx) rats were administered subcutaneous (SC) or intra-amygdala vehicle, E 2, P, or E 2+P. The effects on performance in a test of pain sensitivity, the tailflick task, was observed in animals that experienced an acute exposure to TMT or no odor (control) in a small chamber. Rats that were exposed to TMT had increased tailflick latencies compared to rats not exposed to TMT, this was partially attenuated by the opiate antagonist naloxone. Systemic E 2, P, or E 2+P increased tailflick latencies compared to vehicle administration to ovx rats. Ovx rats administered E 2+P to the amygdala had increased tailflick latencies compared to control rats. These data suggest that following exposure to predator odor, pain sensitivity in the tailflick task is decreased and that E 2 and/or P may have actions in the amygdala to produce similar anti-nociceptive effects.

Spinal pharmacology of antinociception produced by microinjection of μ or δ opioid receptor agonists in the ventromedial medulla of the rat

This study examined the role of spinal GABAergic, serotoninergic and α 2 adrenergic receptors in the antinociception produced by the microinjection of equi-antinociceptive doses of selective opioid receptor agonists in the nucleus raphe magnus (NRM) or the nucleus reticularis gigantocellularis pars α (NGCpα) of the rat. Rats were pretreated with intrathecal administration of either the GABA A receptor antagonist bicuculline, the GABA B receptor antagonist CGP35348, the serotonin 1/2 receptor antagonist methysergide, the α 2 adrenergic receptor antagonist yohimbine or saline. Ten minutes later, either the δ 1 opioid receptor agonist [D-Pen 2,5]enkephalin (DPDPE), δ 2 opioid receptor agonist [D-Ala 2,Glu 4]deltorphin (DELT) or μ opioid receptor agonist [D-Ala 2,NMePhe 4,Gly-ol 5]enkephalin (DAMGO) was microinjected into the NRM, NGCpα or sites in the medulla outside these two regions. The increase in tail-flick latency produced by microinjection of DPDPE into the NRM or NGCpα was antagonized by intrathecal pretreatment with either methysergide or yohimbine. Intrathecal pretreatment with CGP35348 antagonized the antinociception produced by microinjection of DPDPE in the NRM, whereas bicuculline antagonized the antinociception produced by microinjection of DPDPE in the NGCpα. The increase in tail-flick latency produced by microinjection of DELT into the NGCpα, but not the NRM was antagonized by intrathecal pretreatment with yohimbine or CGP35348. Intrathecal pretreatment with methysergide or bicuculline did not antagonize the antinociception produced by microinjection of DELT into either the NRM or the NGCpα. The increase in tail-flick latency produced by microinjection of DAMGO in the NRM was antagonized by intrathecal pretreatment with methysergide or CGP35348, but not by bicuculline or yohimbine. Taken together, these results support the hypothesis that the antinociception produced by activation of δ 1, δ 2 or μ opioid receptors in the rostral ventromedial medulla is mediated by different neural substrates.

Chronic access to a sucrose solution enhances the development of conditioned place preferences for fentanyl and amphetamine in male Long–Evans rats

Consumption of palatable food and fluids alters the behavioral consequences of psychoactive drugs. To further investigate the effects of intake of palatable nutrients on the rewarding properties of these drugs, the effects of chronic intake of a sweet sucrose solution on the development of conditioned place preferences (CPP) to a mu-opioid agonist, fentanyl, and to a stimulant drug, amphetamine, were examined. Male Long–Evans rats consumed laboratory chow and water or chow, water, and a 32% sucrose solution. CPP testing was conducted in a three-chamber apparatus. In Experiment 1 (over four conditioning days), rats received saline, 0.004, or 0.016 mg/kg sc fentanyl citrate before being placed on the nonpreferred side of the apparatus and saline (subcutaneously) before being placed on the preferred side during a separate session on the same day. When given access to all three chambers, rats injected with 0.016 mg/kg fentanyl spent significantly more time on the drug-paired side than rats injected with saline. Furthermore, sucrose-fed rats displayed a significantly greater CPP than chow-fed rats. After conditioning, rats were tested for fentanyl-induced antinociception using the tail-flick test. Using a cumulative dose procedure, fentanyl (0.003, 0.010, 0.030, and 0.100 mg/kg sc) led to dose-dependent increases in tail-flick latencies. Rats fed with sucrose displayed significantly greater responses to fentanyl than those in the chow group. In Experiment 2, rats spent significantly more time on the drug-paired side of the CPP apparatus following injections of 0.33 or 1.0 mg/kg amphetamine than after saline injections. Additionally, following injection of 0.33 mg/kg amphetamine, sucrose-fed rats spent significantly more time on the drug-paired side of the chamber than chow-fed rats.

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.

Effects of temperature and volume on intraperitoneal saline-induced changes in blood pressure, nociception, and neural activity in the rostroventral medulla

ON and OFF cells of the rostral ventromedial medulla are hypothesized to modulate nociception with ON cells facilitating pain and OFF cells inhibiting pain. The current study analyzed the effects of intraperitoneal saline at different volumes and temperatures on nociception (tail flick reflex), blood pressure, and the activity of ON and OFF cells in lightly anesthetized rats. At large volumes (20 cc/kg), room temperature saline excited 7/11 ON cells and inhibited 10/12 OFF cells for 2–5 min. In contrast, large volumes (20 cc/kg) of body temperature saline (37 °C) excited only 1/10 ON cells and inhibited only 3/13 OFF cells, and small volumes (1–2 cc/kg) of room temperature saline excited only 3/10 ON cells and inhibited only 4/11 OFF cells. Tail flick latency increased following saline administration at large volumes with a significant effect of time, but not temperature. The excitation of ON cells and inhibition of OFF cells indicate that cold intraperitoneal saline could be painful and the increase in tail flick latency may indicate a diffuse noxious inhibitory control. It is also possible that the changes in ON and OFF cell activity caused a hyperalgesia that was masked by a simultaneous hypoalgesia that was mediated independent of the ON and OFF cells. Because intraperitoneal saline may produce pain or hyperalgesia, care should be used when saline is used experimentally or clinically.

The importance of tail temperature monitoring during tail-flick test in evaluating the antinociceptive action of volatile anesthetics.

Tail-flick (TF) latency can be influenced by tail-skin temperature (TT), and treatments that raise TT can mimic hyperalgesia on a TF test. As volatile anesthetics can raise TT via heat redistribution, their antinociceptive action can be hidden or obscured in a TF test. We tested the hypothesis that TT monitoring improves the efficiency of TF tests in evaluating the antinociceptive action of volatile anesthetics. The relationship between TT and TF latency was first explored under varied TTs in 12 rats. Then, TT and TF latency were measured before and during isoflurane exposure (1.2%). In the low temperature group (n=6), rats were prewarmed mildly to increase TT during isoflurane exposure. In the high temperature group (n=6), rats were prewarmed enough to prevent a TT increase during isoflurane exposure. There was a highly significant correlation between TT and TF latency, that is, TF latency decreased as TT increased. In the low temperature group, there was a significant increase in TT during isoflurane exposure, while an increase in TF latency did not reach statistical significance. Tail-flick latency corrected by a change in TT showed a significant increase. In the high temperature group, TF latency increased significantly during isoflurane exposure without an increase in TT. Isoflurane inhalation can induce an increase in TT, which can obscure its antinociceptive action as evaluated by a TF test. Monitoring TT during a TF test is important to efficiently evaluate the antinociceptive action of volatile anesthetics.

Antinociceptive effect of cardiopulmonary chemoreceptor and baroreceptor reflex activation in the rat

The effect on the nociceptive tail-flick (TF) reflex of cardiopulmonary chemoreceptor and arterial baroreceptor activation, producing Bezold–Jarisch like- and baro-reflex responses, respectively, was analysed in lightly halothane-anaesthetized rats. Intra-cardiac administration of phenylbiguanide (5–100 μg/kg, into the right atrium) or veratrine (30–150 μg/kg, into the left ventricle), which both elicited the characteristic Bezold–Jarisch-like cardiovascular reflex responses (hypotension and bradycardia), produced a dose-dependent increase in TF latency. A similar inhibitory influence on the TF reflex was noted upon baroreflex activation by acute administration of phenylephrine (15–50 μg/kg i.v.) or aortic depressor nerve stimulation (100–400 μA). As expected from the involvement of local excitatory amino acid receptors in both vagally mediated cardiovascular reflex responses and inhibition of the TF reflex, microinjections of kynurenic acid (3 nmol/0.1 μl), an N-methyl- d-aspartate (NMDA) and non-NMDA receptor antagonist, into the nucleus tractus solitarius, prevented the cardiovascular responses as well as the concomitant increase in TF latency produced by cardiopulmonary chemoreceptor and baroreceptor stimulations. The present data show that induction of the cardiopulmonary chemoreceptor and baroreceptor reflexes produces an antinociceptive effect which can be assessed using the TF test, and that glutamate ionotropic receptors within the nucleus tractus solitarius mediate this effect.

Intrathecal α 2 adrenoceptor agonist clonidine inhibits mechanical transmission in mouse spinal cord via activation of muscarinic M 1 receptors

We examined the role of the spinal muscarinic receptor subtype in the anti-nociceptive effect of intrathecal (i.t.) α 2 adrenoceptor agonist clonidine in mice. I.t. injection of the muscarinic receptor antagonist atropine completely inhibited i.t. clonidine-induced increase in the mechanical threshold, but did not affect the increase in tail-flick latency induced by i.t. clonidine. The clonidine-induced increase in mechanical threshold was inhibited by i.t. injection of the M 1 receptor antagonist pirenzepine in a dose-dependent manner, and by the M 3 receptor antagonist 4-DAMP, but not by the M 2 receptor antagonist methoctramine. The potency of pirenzepine was greater than that of 4-DAMP. These results suggest that the clonidine-induced increase in mechanical threshold is mediated via the activation of M 1 receptors in the spinal cord.

Decrease of the electroacupuncture-induced analgesic effects in nuclear factor-kappa B1 knockout mice

To investigate the involvement of nuclear factor kappa B1 (NF-κB1; p50/p105) in electroacupuncture (EA)-induced analgesia, 2 and 100 Hz EA stimulations were applied at acupoint ST36 (Zusanli) in NF-κB1 knockout mice. EA was performed for 30 min and tail-flick latencies (TFLs) were evaluated every 15 min for 1 h. Wild-type mice displayed a 63.3% increase in TFLs compared to baseline after 2 Hz EA, whereas NF-κB1+/− mice exhibited a 41.8% increase and NF-κB1−/− mice showed only a 3.9% increase of TFLs. The TFLs of 100 Hz EA showed similar trends: a 72.6% increase of TFLs in wild-type, a 38.6% increase in NF-κB1+/− and a 9.3% increase in NF-κB1−/− mice. The present findings suggest that NF-κB1 may play a crucial role in both low and high frequency EA-induced analgesic effects.

The involvement of nitric oxide in the antinociception induced by cyclosporin A in mice

Cyclosporin A (CsA) and other immunophilin-binding agents are known to inactivate neuronal nitric oxide synthase (nNOS). Nitric oxide (NO) is involved in the nociception at the spinal level. We evaluated the effect of acute intraperitoneal (ip) administration of CsA on the tail-flick response in mice and the involvement of NO and opioid receptors in this effect. CsA (5, 10, 20 and 50 mg/kg ip) induced a significant increase in tail-flick response. Nitric oxide synthase (NOS) inhibitor N G-nitro- l-arginine (LNNA; 10, 40 and 80 mg/kg ip) significantly potentiated the CsA-induced (5 mg/kg) increase in tail-flick latency (TFL). While NOS substrate l-arginine (100, 200, 400 mg/kg ip) inhibited the CsA-induced (20 mg/kg) antinociception completely and in a dose-dependent manner. Concomitant administration of l-NNA and l-arginine blocked the inhibition exerted by the latter on the CsA-induced antinociception. The opioid receptor antagonist naloxone (4 mg/kg ip) did not alter the CsA effect. These results indicate that acute administration of CsA induces an antinociceptive effect that involves the l-arginine–NO pathway but is not mediated by opioid receptors.