BACKGROUND: Spinal zaprinast, phospodiesterase inhibitor, has been shown to have an antinociception through an increase of cGMP. The aim of this study was to examine the role of spinal adrenergic and cholinergic receptors on the antinociceptive action of intrathecal zaprinast. METHODS: Rats were implanted with lumbar intrathecal catheters. After formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. After observing the effect of intrathecal zaprinast, antagonism of intrathecal prazosin, yohimbine, atropine and mecamylamine for the effect of zaprinast were evaluated. RESULTS: Intrathecal zaprinast produced a dose-dependent suppression of formalin-induced flinches in both phases of the formalin test. Intrathecal prazosin reversed the antinociception of zaprinast in phase 2, but not phase 1. Intrathecal yohimbine reversed the antinociception of zaprinast in both phases. Neither atropine nor mecamylamine reversed the antinocicetive action of zaprinast. CONCLUSIONS: Intrathecal zaprinast is against the nociceptive state evoked by formalin stimulus. Alpha 2 or alpha 1 adrenergic receptor, but not cholinergic receptors, may be related to the action of zaprinast in the spinal cord.
Animals ; Atropine ; Catheters ; Formaldehyde* ; Mecamylamine ; Pain Measurement* ; Prazosin ; Rats* ; Receptors, Adrenergic, alpha-1 ; Receptors, Cholinergic* ; Spinal Cord ; Yohimbine

Changes of blood pressure, heart rate, ECG, respiration rate and pupil size by intracerebroventricular(ICV) infusion of hypertonic NaCl with 0.04 ml/min for 5 min(total 0.2ml) were observed in urethane-anesthetized rabbits. ICV infusion of 0.75M NaCl produced slight pressor effect (11mmHg) and did not affect other parameters. ICV infusion of 1.5M NaCl began to increase blood pressure from 2~3 min after the infusion and produced maximal increase(24mmHg) at 5~10 min. Then the pressor effect was recovered to the original level at 30~60 min. Change of heart rate by the infusion was not clear, but ST-segment of ECG was markedly depressed. Respiration rate increased about 1.5 times than the control in accordance with the pressor effect and the state was continued even after the recover of the pressor effect. Both pupils dilated markedly and light-reflex was lost. Changes of parameters by ICV infusion of 3.0M NaCl were similar to those by 1.5M NaCl and some rabbits caused severe arrhythmias and died. The purpose of present study is to investigate the mechansim(s) of the pressor effect induced by the ICV infusion of 1.5M NaCl. The pressor effect of 1.5M NaCl was attenuated by the continuous infusion of vasopressin antagonist(20microm/kg/min) but not affected by intravenous treatment with 2mg/kg phentolamine, 2mg/kg propranolol and 1mg/kg chlorisondamine. The pressor effect was not altered with ICV 0.12mg/kg phenoxybenzamine, 0.4mg diltiazem, 0.1mg/kg mecamylamine and 0.2mg/kg atropine. After ICV infusion of 25microg/kg/min of diazepam, however, the pressor effect was completely abolished and restored 3~4 hours after stopping diazepam infusion. The pressor effect was rather potentiated than inhibited in bilateral adrenalectomized or nephrectomized rabbits. Infusion of 2microg/kg/min of saralasin for 10 min in the bliateral adrenalectomized rabbit did not affect the pressor effect at all. These results suggest that hypertensive effect induced by ICV infusion of hypertonic NaCl is mediated by the increase of vasopressin secretion.
Arrhythmias, Cardiac ; Atropine ; Blood Pressure ; Chlorisondamine ; Diazepam ; Diltiazem ; Electrocardiography ; Heart Rate ; Infusions, Intraventricular* ; Mecamylamine ; Phenoxybenzamine ; Phentolamine ; Propranolol ; Pupil ; Rabbits* ; Respiratory Rate ; Saralasin ; Vasopressins

Effects of a M1 receptor antagonist, pirenzepine, a M2 receptor antagonist, AF-DX116, and a nicotinic receptor antagonist, mecamylamine on the pressor responses to preganglionic sympathetic nerve stimulation(PNS) and McN-A-343 and DMPP in spinal(pithed) rabbits were investigated in order to elucidate a functional role of M1, M2 and nicotinic receptors in ganglionic transmission. Pirenzepine and AF-DX116 selectively inhibited the McN-A-343-induced pressor reponse in chlorisondamine-treated rabbit and the BCh-induced bradycardia, respectively. Electrical stimulations of preganglionic sympathetic outflow at T8 level produced increases in blood pressure. Pirenzepine(3 microgram/kg) significantly inhibited the PNS-induced pressor response and the degree of inhibition was not changed by increasing the doses to 100 microgram/kg. AF-DX116(100 microgram/kg) had no effect on the PNS-induced pressor response. Mecamylamine inhibited the PNS-induced pressor response in a dose-dependent manner. The inhibitory action of mecamylamine was significantly augmented by combined-treatment with pirenzepine(30 microgram/kg) but AF-DX116(100 microgram/kg) did not affect the inhibitory action of mecamylamine. McN-A-343 and DMPP elicited pressor response in the spinal rabbit. Pirenzepine and AF-DX116 dose-dependently inhibited the McN-A-343-induced pressor response but they did not affect DMPP-induced pressor response. Mecamylamine inhibited both pressor responses induced by Mc-N-343- and DMPP. These results suggest that not only nicotinic receptors but also M1 receptors play a facilitatory role in ganglionic transmission but M2 receptors do not contribute the transmission in spinal(pithed) rabbits.
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride ; Blood Pressure ; Bradycardia ; Dimethylphenylpiperazinium Iodide ; Electric Stimulation ; Ganglia, Sympathetic* ; Ganglion Cysts ; Mecamylamine ; Pirenzepine ; Rabbits ; Receptors, Nicotinic*

BACKGROUND: Intrathecal gabapentin is effective on nociceptive states evoked by tissue injury. In addition, gabapentin interacts synergistically with clonidine at the spinal level, suggesting that a mechanism of gabapentin may be related to spinal adrenoceptors. However, it has not been established whether this drug is associated with cholinergic receptors. The aim of this study was to examine the role of spinal adrenergic and cholinergic receptors on the antinociceptive action of intrathecal gabapentin. METHODS: Rats were implanted with lumbar intrathecal catheters. For a nociceptive test, 50nl of 5% formalin solution was injected into the hindpaw. The effect of intrathecal gabapentin, administered 10 min before the formalin injection, was assessed. Next, antagonistic effects of intrathecal prazosin, yohimbine, atropine and mecamylamine for the action of intrathecal gabapentin were evaluated. RESULTS: Formalin injection caused a biphasic incidence of flinching of the injected paw. Intrathecal gabapentin produced a dose-dependent suppression of only the phase 2 flinching response in the formalin test. Intrathecal atropine, but not prazosin, yohimbine nor mecamylamine, reversed the antinociception of intrathecal gabapentin. CONCLUSIONS: The antinociceptive effect of intrathecal gabapentin on facilitated states may be mediated through the muscarinic receptor but by neither the nicotinic receptor nor the adrenergic receptor at the spinal level.
Animals ; Atropine ; Catheters ; Cholinergic Antagonists* ; Clonidine ; Formaldehyde ; Incidence ; Mecamylamine ; Nociception ; Pain Measurement ; Prazosin ; Rats ; Receptors, Adrenergic ; Receptors, Cholinergic ; Receptors, Muscarinic ; Receptors, Nicotinic ; Spinal Cord ; Yohimbine

The effects of antihypertensive drugs on the choroidal blood flow in rabbits were studied by an apparatus based on the principle of internal calorimetry of Grayson. Thermistors, as the sensing elements, were fastened on the scleral surface of the eye, and determinations were performed up to 60 minutes after intravenous administrations of drugs. The drugs studied were: ganglion blocking agents (pentholinium tartarate, 4 mg; hexamethonium bromide, 1 mg; and mecamylamine chloride, 0.15mg), alpha-methyldopa, 4 mg; guanethidine, 0.5 mg; reserpine, 0.2 mg; hydralazine, 5 mg; and diuretics (dichlorothiazide, 2.5 mg; frusemide, 2.5 mg). Except the diuretics, all the drugs employed produced considerable increase in the choroidal blood flow. The relationships between blood pressure, intraocular pressure and the choroidal blood flow were discussed and the clinical applications were suggested.
Administration, Intravenous ; Antihypertensive Agents* ; Blood Pressure ; Calorimetry ; Choroid* ; Dental Calculus ; Diuretics ; Furosemide ; Ganglion Cysts ; Guanethidine ; Hexamethonium ; Hydralazine ; Intraocular Pressure ; Mecamylamine ; Methyldopa ; Rabbits* ; Reserpine

BACKGROUND: Peripheral nerve injury may produce a syndrome consisting of spontaneous pain, allodynia and hyperpathia. Cholinesterase inhibitors are known to have an antinociceptive effect in hot plate and tail flick tests and to be mediated by spinal muscarinic system. The purpose of the current study was to determine the effect of intrathecally (i.t.) administered edrophonium and neostigmine on the touch-evoked allodynia and to identify the antagonism of antiallodynia in a rat model of neuropathic pain. METHODS: Sprague Dawley rats were prepared with tight ligation of left L5/L6 spinal nerves with 6~0 black silk and chronic lumbar intrathecal catheters. After obtaining the baseline hindpaw withdrawal scores, edrophonium (3~100ug) or neostigmine (0.3~10ug) was administered intrathecally. Tactile allodynia was measured using von Frey filaments and allodynic threshold was calculated by updown method. Motor dysfunction was assessed by observing righting/stepping reflex responses and abnormal weight bearing. To examine the reversal of antiallod ynia, muscarinic receptor antagonist atropine (10ug) or nicotinic receptor antagonist mecamylamine (10ug) was injected intrathecally 5 min. prior to injection of edrophonium or neostigmine. RESULTS: I.t. edrophonium and i.t. neostigmine produced a dose dependent antagonism of allodynic state but had moderate to severe effect on motor weakness at doses of 3 and 10 g of neostigmine. Pretreatment with i.t. atropine yielded a complete antagonism of antiallodynia in both drugs, but i.t. mecamylamine did not significantly reverse incresed allodynic threshold. CONCLUSIONS: These experiments suggest that i.t. edrophonium or i.t. neostigmine produces a dose dependent antagonism on touch-evoked allodynia at the spinal level and this antagonism is likely due to spinal muscarinic system.
Atropine ; Catheters ; Cholinesterase Inhibitors ; Edrophonium* ; Hyperalgesia ; Ligation ; Mecamylamine ; Models, Animal ; Neostigmine* ; Neuralgia* ; Peripheral Nerve Injuries ; Rats, Sprague-Dawley ; Receptors, Muscarinic ; Receptors, Nicotinic ; Reflex ; Silk ; Spinal Nerves ; Weight-Bearing

BACKGROUND: Peripheral nerve injury may produce a syndrome consisting of spontaneous pain, allodynia and hyperpathia. In previous study, we examined the antiallodynic action produced by intrathecal (i.t.) cholinesterase inhibitors (ChEi) in a neuropathic pain rat model and the reversal of antiallodynic state by i.t. atropine, muscarinic antagonist, but not by nicotinic antagonist mecamylamine. The purpose of this study was to determine the selective antagonistic action of four subtypes of muscarinic receptor on antiallodynic state by i.t. ChEi in a rat model of neuropathic pain. METHODS: Sprague Dawley rats were prepared with tight ligation of left L5/L6 spinal nerves with 6-0 black silk and chronic lumbar intrathecal catheters. After obtaining the baseline hindpaw withdrawal scores, edrophonium (100 microgram) or neostigmine (10 microgram) was administered intrathecally. Tactile allodynia was measured using von Frey filaments and allodynic threshold was calculated by the up-down method. Allodynic changes were tested at 15, 30, 45, 60, 90, 120 and 180 minutes. To examine the reversal of antiallodynia and to compare the antagonizing action of antiallodynic state produced by i.t. administration of ChEi, non-selective muscarinic receptor antagonists atropine (10 microgram), M1 antagonist pirenzepine (3 microgram), M2 antagonist methoctramine (3 microgram), M3 antagonist 4-DAMP (3 microgram) and M4 antagonist tropicamide (3 microgram) were injected intrathecally respectively 5 minutes prior to the injection of edrophonium or neostigmine. RESULTS: Antiallodynia produced by i.t. edrophonium was reversed by pretreatment with i.t. methoctramine, 4-DAMP, tropicamide and pirenzepine (P<0.05). On the contrary, antiallodynic state made by i.t. neostigmine was not antagonized by methoctramine, 4-DAMP and tropicamide. M1 antagonist pirenzepine had a moderate, statistically significant (P<0.05) effect on reversal of increased allodynic threshold while atropine showed a complete antagonism. CONCLUSION: These experiments suggest that antialllodynic action of cholinesterase inhibitors is likely due to mediation of spinal muscarinic system and M1 receptor subtype is more likely involved in this mechanism.
Animals ; Atropine ; Catheters ; Cholinesterase Inhibitors ; Edrophonium ; Hyperalgesia ; Ligation ; Mecamylamine ; Models, Animal* ; Negotiating ; Neostigmine ; Neuralgia* ; Peripheral Nerve Injuries ; Pirenzepine ; Rats* ; Rats, Sprague-Dawley ; Receptors, Muscarinic* ; Silk ; Spinal Nerves ; Tropicamide

BACKGROUND: Experimental evidence indicates that ginseng modulate the nociceptive transmission. Authors examined the role of adrenergic and cholinergic receptors on the antinociceptive action of Korean red ginseng against the formalin-induced pain at the spinal level. METHODS: Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. Fifty microl of 5% formalin solution was injected to the hindpaw for induction of pain and formalin-induced pain (flinching response) was observed. The role of spinal adrenergic and cholinergic receptors on the effect of Korean red ginseng was assessed by antagonists (prazosin, yohimbine, atropine and mecamylamine). RESULTS: Intrathecal Korean red ginseng produced a dose-dependent suppression of the flinching response in the rat formalin test. All of prazosin, yohimbine, atropine and mecamylamine antagonized the antinociception of Korean red ginseng. CONCLUSIONS: Spinal Korean red ginseng is effective against acute pain and facilitated pain state evoked by formalin injection. All of alpha 1, alpha 2, muscarinic and nicotinic receptors may play an important role in the antinociceptive action of Korean red ginseng at the spinal level.
Acute Pain ; Animals ; Atropine ; Catheters ; Formaldehyde ; Humans ; Male ; Mecamylamine ; Pain Measurement ; Panax ; Prazosin ; Rats ; Rats, Sprague-Dawley ; Receptors, Cholinergic ; Receptors, Nicotinic ; Spinal Cord ; Yohimbine

BACKGROUND: The effect of spinal adrenergic and cholinergic receptors on the anti-nociceptive effect of intrathecal ginsenosides was determined in a rat postoperative pain model. METHODS: Catheters were placed into the intrathecal space of male Sprague-Dawley rats. Postoperative pain was evoked by an incision to the plantar surface of a hind paw. Withdrawal thresholds was used as a nociceptive parameter and was measured with a von Frey filament. After observing the effect of intrathecal ginsenosides, an alpha-1 adrenergic receptor antagonist (prazosin), an alpha-2 adrenergic receptor antagonist (yohimbine), a muscarinic acetylcholine receptor antagonist (atropine), and a nicotinic acetylcholine receptor antagonist (mecamylamine) were given 10 min before administration of the ginsenosides to analyze the contribution of spinal adrenergic and cholinergic receptors on the antinociceptive effect of ginsenosides. RESULTS: Paw incision decreased withdrawal threshold in incised site of paw, but no change of withdrawal threshold was not seen in non-incised site. The intrathecal ginsenosides increased withdrawal threshold of the incised paw in a dose-dependent manner. Pre-treatment with both prazosin and intrathecal yohimbine antagonized the anti-nociceptive effect of the ginsenosides. However, pre-treatments with atropine or mecamylamine had any effect on the antinociceptive activity of ginsenosides. CONCLUSIONS: Intrathecal ginsenosides are effective in attenuation of postoperative pain induced in the rat model. Anti-nociceptive action of ginsenosides is partially mediated by spinal adrenergic receptors, but does not appear to be related to spinal cholinergic receptors.
Animals ; Atropine ; Catheters ; Ginsenosides ; Humans ; Male ; Mecamylamine ; Pain, Postoperative ; Prazosin ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic ; Receptors, Adrenergic, alpha-1 ; Receptors, Adrenergic, alpha-2 ; Receptors, Cholinergic ; Receptors, Muscarinic ; Receptors, Nicotinic ; Spinal Cord ; Yohimbine

BACKGROUND: The influence of gamma-aminobutyric acid(GABA), which is well-known as a major inhibitory neurotransmitter in central nervous system, on secretion of catecholamines(CA) was investigated in the isolated perfused rat adrenal gland. METHODS: Mature male Sprague-Dawley rats were anesthetized with ether. Ther adrenal gland was isolated by the methods f Wakade. A cannula used for perfusion of the adrenal gladn was inserted into the distal end of the renal vein. The adrenal gland, along with ligated blood vessels and the cannula, was carefully removed from the animal and placed on a platform of a leucite chamber. RESULTS: GABA given into an adrenal vein of the rat produced markedly secretion of CA from the adrenal gland. Tachyphylaxis to the relesing effect of CA evoked by GABA was observed. The secretory effect of CA evoked by GABA was attenuated singnificantly by pretreatment with mecamylamine or atropine. Ouabain inhibited greatly the secretory response of GABA. When omitting the external potassium ion, the basal release of CA was increased. During this period GABA no longer revealed the increase in CA release. CA secretion evoked by GABA was blocked significantly by perfusion of calcium-free Krebs solution containing 5mMEGTA for 30-min. Pretreatment with bicuculline or picrotoxin inhibited CA secretion evoked by GABA as well as ACh. ACh-evoked CA release was potentiated by GABA infusion(400ug/30min). CONCLUSION: The experimental findings suggest that GABA causes the secretory effect of CA in a fashion of external calcium and potassium iosn-dependence, and that this releasing effect of CA induced by GABA may be exterted by stimulation of GABAergic A-reccptors located on adrenomedullary chromaffine cell, which is likely associated with cholinergic receptor activation evoked CA secretion.
Adrenal Glands* ; Animals ; Atropine ; Bicuculline ; Blood Vessels ; Calcium ; Catheters ; Central Nervous System ; Ether ; gamma-Aminobutyric Acid ; Humans ; Male ; Mecamylamine ; Neurotransmitter Agents ; Ouabain ; Perfusion ; Picrotoxin ; Potassium ; Rats* ; Rats, Sprague-Dawley ; Renal Veins ; Tachyphylaxis ; Veins