Straub Tail Reaction In Mice Research Articles

Morphine-induced Straub tail reaction in mice treated with serotonergic compounds

Constitutively active 5-HT2 receptors have been suggested to contribute to motoneuronal excitability, muscle spasms and spasticity. Accordingly, 5-HT2C receptor inverse agonists have been demonstrated in pilot experiments to reduce spasticity in animal model of spasticity and patients with spinal cord injuries. Thus, 5-HT2C receptor inverse agonists may represent a novel class of anti-spasticity agents justifying a search for compounds with robust 5-HT2C receptor inverse agonist activity either among the existing medications or via a dedicated drug discovery program. Morphine-induced Straub tail response in mice is regarded as a model of transient spasticity that may be suitable for supporting such drug discovery efforts. Subcutaneous injection of morphine (10–60mg/kg) induced a dose-dependent Straub tail reaction in male Swiss mice with maximum response obtained 15–30min after the morphine administration. When given prior to morphine, 5-HT2B/2C receptor inverse agonists cyproheptadine (1–10mg/kg, i.p.) and SB206553 (0.3–3mg/kg, i.p.) diminished Straub tail reaction dose-dependently without affecting spontaneous locomotor activity. In contrast, 5-HT2B/2C receptor antagonist methysergide (1–5.6mg/kg, i.p.) and 5-HT2C receptor antagonist SB242084 (1–5.6mg/kg, i.p.) as well as 5-HT2A receptor inverse agonist pimavanserin (1–10mg/kg, i.p.) had no appreciable effects on Straub tail response. Taken together, the findings indicate that constitutive activity of 5-HT2B/2C receptor may be involved in the mechanisms of morphine-induced spasticity. Thus, morphine-induced Straub tail response may be evaluated further as a candidate higher throughput test to identify 5-HT2C receptor inverse agonists with anti-spasticity effects in vivo.

Straub tail reaction in mice treated with σ1 receptor antagonist in combination with methamphetamine

Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific σ receptor antagonist) and methamphetamine (METH). The intensity and duration of STR depended on the dose of BMY 14802. The tail reaction was inhibited completely by (+)-SKF 10,047 (a putative σ(1) receptor agonist) and partially by PB 28 (a putative σ(2) receptor agonist). The STR was mimicked in mice treated with BD 1047 (a putative σ(1) receptor antagonist), but not SM-21, a putative σ(2) receptor antagonist, in combination with METH. STR evoked with BD 1047 plus METH was inhibited by (+)-SKF 10,047. STR induced by BMY 14802 and METH was abolished by naloxone (a relatively non-selective opioid receptor antagonist) or U-50,488H (a selective κ-agonist), suggesting that the STR may be mediated by activation of opioid receptor system.

Different modes of action of morphine and epibatidine in Straub tail reactions in mice.

The Straub tail reaction in mice is an S-shaped dorsiflexion of the mouse tail, long known as a sensitive and specific bioassay for morphine (CAS 57-27-2). It is based on a contraction of the sacro-coccygeal dorsalis muscles. In the case of morphine the reaction is thought to be induced by a long-lasting stimulation of the muscle's motor innervation at the level of the lumbosacral spinal cord. A similar reaction caused by epibatidine differs pharmacologically, because in this case the reaction can be specifically inhibited by the ganglionic blocking agent mecamylamine. This points to a site of action of epibatidine (CAS 140111-52-0) at the neuromuscular junction of the sacro-coccygeal dorsalis muscles and requires the presence of muscle fibres which react to depolarization by sustained contraction. The present study provides evidence of the existence of such fibres using histochemical and immunohistochemical methods.

Straub tail reaction in mice treated with sigma 1 receptor antagonist in combination with methamphetamine

Straub tail reaction in mice treated with sigma 1 receptor antagonist in combination with methamphetamine

Stimulation of either cholecystokinin receptor subtype reduces while antagonists potentiate or sensitize a morphine-induced excitatory response

Cholecystokinin peptides (CCK) have been shown to antagonize many opioid-mediated effects. The present study was undertaken to determine whether peripheral injections of cholecystokinin sulphated octapeptide (CCK8), cholecystokinin tetrapeptide (CCK4), the CCK 1 (lorglumide) and the CCK 2 (PD-135,158 and LY-225910) receptor antagonists can influence a classic morphine excitatory effect, i.e. the display of Straub tail reaction in mice (STR). A total of 570 female Balb/C mice were tested. Experiment 1 was undertaken to determine whether i.p. injections of CCK8 or CCK4 can influence STR. Each animal was treated with i.p. injections of saline or CCK8 (10 and 20 nmol/kg) or CCK4 (20 and 40 nmol/kg). After 30 min all animals received an i.p. injection of morphine hydrochloride (10.0 mg/kg). The highest doses of both CCK8 (35% STR) and CCK4 (40% STR) significantly reduced STR as compared to saline (85% STR) treated mice (Fisher test; P < 0.01). In experiment 2 each animal was treated with ip injections of saline or 1.0 mg/kg lorglumide or PD-135,158 fifteen minutes before an injection of morphine at doses ranging from 1.0 to 50.0 mg/kg. In experiment 3 animals were treated with injections of saline, 0.1 or 10.0 mg/kg lorglumide or LY-225910 before an injection of a fixed MC dose (2.0 mg/kg). Both lorglumide and PD-135,158 induced a significant shift to the left in the morphine dose-response curves as well as a significant decrease in ED50 of the STR. ED50 for lorglumide was significantly lower than ED50 for PD-135,158. Both doses of lorglumide and the highest dose of LY-225910 significantly increased the percent of animals displaying STR. Experiment 4 was undertaken to determine whether repeated peripheral injections of morphine or the morphine-potentiating agents CCK 1 (lorglumide) and the CCK 2 (LY-225910) receptor antagonists can induce morphine sensitization. Each animal was treated with 5 daily i.p. injections of saline (control group), 1.5 mg/Kg morphine hydrochloride (group morphine), and 1.0 mg/Kg lorglumide (group LOR) or LY-225910 (group LY). One, two, three and four weeks after the last treatment day, all animals were challenged with one i.p. injection of morphine (1.5 mg/Kg). The morphine, LOR groups and group LY showed a significant increase in percentage of animals displaying STR. These data demonstrate that the blockade of endogenous CCK actions leads to morphine sensitization probably through both CCK receptors. The present data are consistent with the antagonistic effects of CCK and opioids in the control of morphine-induced STR. In addition, these results suggest that both CCK receptors are involved in the modulatory effects of CCK on this morphine effect.

On the mechanism of tolerance to morphine-induced Straub tail reaction in mice

The effect of 5-HT and opioid receptor antagonists on morphine-induced Straub tail was studied in mice. Straub tail behavior was induced by subcutaneous administration of different doses (20, 30, and 40 mg/kg) of morphine hydrochloride to mice. The effect of morphine was dose-dependent. Maximum response was obtained with 40 mg/kg of the drug. The response induced by morphine (20 and 40 mg/kg) was decreased by different doses of intraperitoneal injection of naloxone (1 and 2 mg/kg) or methysergide, mianserin, and ritanserin (1 and 2 mg/kg). The effect of morphine (40 mg/kg) was also reduced by intracerebroventricular injection of naloxone (0.4–0.8 μg/animal) or mianserin (2 and 4 μg/animal). Different groups of mice received one daily dose (50 mg/kg sc) of morphine sulfate for 3 days to develop tolerance to morphine. The Straub tail reaction induced by morphine hydrochloride (40 mg/kg) was tested on the fourth day. Naloxone injection (1 and 2 mg/kg ip) on Day 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), decreased tolerance induced to morphine. Methysergide, mianserin, or ritanserin (intraperitoneal) on Days 2 and 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), also decreased tolerance induced to morphine. Intracerebroventricular injection of either naloxone or mianserin also reduced tolerance to morphine. It is concluded that 5-HT 2 and opioid receptor mechanisms are involved in morphine-induced Straub tail reaction and tolerance induced to morphine also may be mediated through these receptors.

Epibatidine: high potency and broad spectrum activity on neuronal and neuromuscular nicotinic acetylcholine receptors.

The activity of epibatidine at neuronal and neuromuscular nicotinic acetylcholine receptors was investigated in several in situ and in vitro systems and compared with the activity of nicotine and suxamethonium. Activation of ganglionic nicotinic receptors by epibatidine was shown in the guinea-pig ileum (contraction mediated by the cholinergic neurons of the ileum) and in pithed and atropinized rats (rise in blood pressure). Epibatidine also activated nicotinic receptors at the peripheral terminals of afferent C-fibres (rabbit ear) and in the brain (antidiuresis in rats). The agonistic effects of epibatidine were followed by long-lasting receptor desensitization. No antinociceptive effect of epibatidine was seen in rats at a dose free of motor impairment. On muscle end plate nicotinic receptors of the rat diaphragm (not responding to depolarizing agents by contraction), epibatidine was equipotent with suxamethonium in causing neuromuscular inhibition. On an extraocular muscle of the rabbit (responding to depolarizing agents by contraction) epibatidine in vitro and in situ caused a contraction at a 100-fold lower dose than suxamethonium. The Straub tail reaction in mice to epibatidine could be attributed to the sustained stimulation of motor end plate receptors of the "slow contracting" type of muscle fibres by epibatidine. In conclusion epibatidine was the most potent agonist on all neuronal and neuromuscular nicotinic receptors examined.

Possible involvement of protein kinase C in the attenuation of the morphine-induced Straub tail reaction in diabetic mice

To investigate the role of protein kinase C in the attenuation of the morphine-induced Straub tail reaction in diabetic mice, we examined the effects of protein kinase C activator or inhibitor on the i.c.v. morphine-induced Straub tail reaction in mice. This reaction was less in diabetic mice than in normal mice. Intracerebroventricular pretreatment with phorbol 12,13-dibutyrate (50 pmol), a potent protein kinase C activator, attenuated the morphine-induced Straub tail reaction in normal mice, but not in diabetic mice. I.c.v. pretreatment with calphostin C (10 pmol), a selective protein kinase C inhibitor, enhanced the reaction in diabetic mice, but not in normal mice. The dose-response curve for the morphine-induced Straub tail reaction in normal mice, but not in diabetic mice, was shifted to the right by i.c.v. pretreatment with phorbol 12,13-dibutyrate (50 pmol). Furthermore, i.c.v. pretreatment with calphostin C (3 pmol) shifted the dose-response curve to the left in diabetic mice, but not in normal mice. These results indicate that activation of protein kinase C reduces the morphine-induced Straub tail reaction in normal mice. Also, the attenuation of the morphine-induced Straub tail reaction in diabetic mice may be due in part to increased protein kinase C activity.

Effects of diabetes on the morphine-induced Straub tail reaction in mice

The effects of diabetes on the morphine-induced Straub tail reaction were examined in mice. The Straub tail reaction induced by s.c. administration of morphine was significantly less in diabetic mice than in non-diabetic mice. The morphine-induced Straub tail reaction was significantly reduced following pretreatment with β-funaltrexamine, a selective μ-opioid receptor antagonist, in both diabetic and non-diabetic mice. Furthermore, the morphine-induced Straub tail reaction was also significantly reduced in both diabetic and non-diabetic mice following pretreatment with naloxonazine, a selective μ 1-opioid receptor antagonist. These results suggest that mice with diabetes are hypo-responsive to μ 1-opioid receptor-mediated Straub tail reaction.

Effects of yohimbine and naltrexone in counteraction of the morphine straub tail and the amphetamine-potentiated morphine straub tail in mice

The alpha-adrenergic blocking agent, yohimbine, prevented the production of the morphine Straub tail reaction in mice, although on a mg dose basis it was only about 1 400 as potent as the narcotic antagonist naltrexone by subcutaneous injection. Likewise, yohimbine prevented the potentiation of the morphine Straub tail reaction by amphetamine, being about 1 170 as active as naltrexone. Preliminary studies with another alpha-adrenergic blocking agent, phentolamine, indicated that it also inhibited the production of the Straub tail reaction by morphine, although it appeared to be somewhat weaker than yohimbine in this respect. These results suggest the involvement of alpha-adrenergic mechanisms in the production of the morphine Straub tail reaction and in the potentiation of the morphine Straub tail reaction by amphetamine.

Pharmacological action of eptazocine (l-1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine). (III) Central action of eptazocine (author's transl)

Pharmacological actions of eptazocine on the central nervous system were investigated by pharmacological and behavioral methods. Eptazocine produced sedation at low doses and Straub tail reaction in mice and ataxia in rats at high doses. In mice, eptazocine caused decreases in the spontaneous locomotor activities measured by the wheel cage and Animex methods, but caused an increase of the response in rats as determined by the open-field method. Eptazocine caused impairment of performance in the rotarod test and the traction test in mice, a decrease of activity of EMG, and an inhibition of flexor reflex in rats. Eptazocine decreased body temperature, potentiated pentobarbital-induced sleeping, and convulsion caused by pentylene-tetrazol in mice. Fighting behavior induced by electric shock and central stimulation effect of methamphetamine were inhibited by eptazocine in mice. Eptazocine showed an inhibiton of avoidance behavior in shuttle and skinner boxes in rats. These results suggest that eptazocine produces a non-specific inhibitory action on the central nervous system.

Agonist—antagonist properties of phenoxybenzamine in antinociception and opiate dependence tests

The doe—response curve for phenoxybenzamine inhibition of stereospecific 3H-naloxone binding in brain homogenates was found to shift to the right in the presence of 100 mM NaCl. From the ratios of the IC 50 in the presence of Na + to the IC 50 in the presence of Na + calculated in this study for phenoxybenzine and some opiates it was predicted that phenoxybenzamine would have mixed agonist—antagonist properties in antinociceoption and that its antagonist activity would be in the rank order: butorphanol (1.8) ⪢ phenoxybenzamine (4.3) > M2230 (5.7) > pentazocine (6.9) ⪢ levorphanol (13.6). Phenoxybenzamine antagonized the oxymorphone-induced Straub tail reaction in mice and induced the abstinence syndrome in non-withdrawn morpine-dependent mice as predicted by the Na + response ratio. In the mouse tail flick assay phenoxybenzamine acted like the mized agonist—antagonist benzomorphinas as predicted. In “physical dependence capabilty” phenoxybenzamine was intermediate between butorphanol and pentazocine as predicted by the Na + response ratios. The success of the Na + response ratio derived from phenoxybenzamine's properties in the vitro opiate binding assay in predicting the behavior and rank order of phenoxybenzamine in in vivo tests, plus the ability of naloxone to antagonize phenoxybenzamine's antinociceptive action suggest that phenoxybenzamine's antinociceptive action may be mediated by the brain opiate receptor rather than by central α-adrenergic receptor blockade.

Effect of centrally acting muscle relaxants on the morphine-induced Straub tail reaction in mice.

This investigation was carried out in an attempt to ascertain whether all narcotic analgesics produce the Straub tail reaction (STR), and whether the morphine-induced STR could be depressed by centrally acting muscle relaxants. Morphine, oxycodone and levorphanol elicited the STR dose-dependently but codeine, pethidine and pentazocine gave only slight STR. The peak time of the STR was 30 min after the administration of morphine. Intracerebral injection of morphine evoked the STR, but not markedly. Naloxone and pentazocine depressed the morphine-induced STR considerably. Chlordiazepoxide, diazepam, oxazepam, carisoprodol, chlormezanone, chlorzoxazone, meprobamate, orphenadrine, chlorpromazine, perphenazine and haloperidol also reduced the morphine-induced STR markedly. The morphine-induced STR was inhibited noticeably by intracerebral or systemic injection of baclofen and difenamizole. The intracerebral dose of baclofen required for this inhibition was as low as approximately one-thousandth of that by systemic administration. These findings suggest that the morphine-induced STR is positively depressed by centrally acting muscle relaxants.

Effects of various amino acids and their related agents in association with neurotransmitter substances on the morphine-induced Straub tail reaction in mice.

Experiments were carried out in an attempt to elucidate the effects of various amino acids and their related agents in association with neurotransmitter substances on the morphine-induced Straub tail reaction (STR) in mice, using intracerebral injection technique. γ-Aminobutyric acid (GABA) and aminooxyacetic acid yielded significant decrement of the STR. Bicuculline provided the significant increment of the STR. DL-γ-Amino-β-hydroxybutyric acid and γ-guanidinobutyric acid had no influence on the STR. Glycine and taurine inhibited the STR significantly. L-Glutamic acid, L-aspartic acid, L-tyrosine and L-tryptophan had no influence on the STR. These results suggested the possibility that GABA, glycine and taurine may prevent the morphine-induced STR by means of an inhibitory action on the central nervous system in mice.

Effects of opiates and opiate antagonists on the Straub tail reaction in mice.

1. Subcutaneous injections of opiates produced the Straub tail reaction in mice. The potencies of the opiates in mice were consistent with previous estimates of the analgesic potencies in animals and in man.2. The potencies of sixteen antagonists in counteracting the reaction were consistent with those previously obtained with the rat tail-flick test.3. The (-) isomers of four benzomorphan derivatives were much more potent in counteracting the reaction than their (+) isomers and about twice as potent as their racemates. The activity of the isomers seemed to follow Pfeiffer's rule: the lower the effective dose of a drug, the greater the difference in the pharmacological effects of the optical isomers. One of the trans isomers acted like an opiate, while its cis isomer acted like an antagonist.4. Naloxone and nalorphine fulfilled conventional criteria for competitive antagonism, whereas atropine and the (-) and the (+) isomers of pentazocine and of cyclazocine did not do so.5. The Straub tail test seems to be useful for studying structure-activity relations among opiates and opiate antagonists.