Spinal alpha-2 adrenoceptors and cholinergic receptors are involved in the regulation of acute nociception and the facilitated processing. The aim of this study was to examine the pharmacological effect of an intrathecal alpha-2 agonist and a cholinesterase inhibitor on the facilitated pain model induced by formalin injection and to determine the nature of drug interaction using an isobolographic analysis. Both intrathecal clonidine and neostigmine dose-dependently suppressed the flinching during phase 1 and phase 2. Intrathecal pretreatment with atropine reversed the antinociceptive effects of clonidine and neostigmine in both phases. Pretreatment with intrathecal yohimbine attenuated the effect of clonidine. The antinociception of clonidine and neostigmine was not reversed by mecamylamine. Isobolographic analysis showed that intrathecal clonidine and neostigmine acted synergistically in both phase 1 and 2. Intrathecal pretreatment with atropine and yohimbine antagonized the effect of the mixture of clonidine and neostigmine in both phases, but no antagonism was observed with mecamylamine pretreatment. These data indicate that spinal clonidine and neostigmine are effective to counteract the facilitated state evoked formalin stimulus, and these two drugs interact in a synergistic fashion. In addition, the analgesic action of intrathecal clonidine is mediated by spinal muscarinic receptors as well as alpha-2 adrenoceptors.
Adrenergic alpha-Agonists/*pharmacology ; Analgesics, Non-Narcotic/*pharmacology ; Animal ; Cholinesterase Inhibitors/*pharmacology ; Clonidine/administration & dosage/*pharmacology ; Dose-Response Relationship, Drug ; Drug Synergism ; Formaldehyde ; Injections, Spinal ; Male ; Neostigmine/administration & dosage/*pharmacology ; Pain/drug therapy ; Rats ; Rats, Sprague-Dawley

The intraocular pressure (IOP) of glaucomatocyclitic crisis with the attack fell 50.3%, from 37.8 +/- 8.2 mmHg to 18.8 +/- 4.8 mmHg, 4 hours after instillation of 1% apraclonidine. Glaucomatocyclitic crisis showed a more significant hypotensive response to 1% apraclonidine than primary open-angle glaucoma (24.8%, from 43. 1 +/- 8.1 mmHg to 32.4 +/- 7.5 mmHg after 4 hours). The intraocular pressure decrease percentage was similar regardless of the initial level of intraocular pressure. Clinically significant changes in mean systolic and diastolic blood pressures, were not observed, however, a mild decrease in the pulse rate was noted. And the local mydriatic effect on the pupillary diameter was significant. Apraclonidine, 1% might be newly indicated to control the IOP rise of glaucomatocyclitic crisis. Further studies on the possible mechanism of the prostaglandin mediated hypotensive effect of 1% apraclonidine are suggested.
Adolescent ; Adrenergic alpha-Agonists/*administration & dosage ; Adult ; Aged ; Clonidine/administration & dosage/*analogs & derivatives ; Female ; Glaucoma, Open-Angle/drug therapy ; Hemodynamics ; Humans ; Intraocular Pressure ; Iridocyclitis/*drug therapy ; Male ; Middle Aged ; Ocular Hypertension/*drug therapy ; Ophthalmic Solutions ; Syndrome

OBJECTIVETo evaluate the effect of dexmedetomidine (Dex) on bispectral index (BIS) and auditory evoked potential index (AAI) during anesthesia with target controlled infusion (TCI) of propofol and remifentanyl.

METHODSThirty adult patients (ASA I approximate, equalsII) who were scheduled for elective thyroidectomy were monitored with BIS, AAI, ECG, blood pressure, end-tidal CO(2), and pulse oximeter before and during anesthesia. Anesthesia was induced by TCI with propofol 4 mg/L and remifentanyl 1 mu g/kg. After loss of consciousness the patients were intubated after rocuronium 0.6 mg/kg intravenous injection, remifentanyl was then infused at 0.2 microg/(kg x min)(-1) and propofol infusion (Ct) was titrated to maintain a BIS value at 50 +/- 3. At 10 min after stabilization of anesthesia the patients were randomly and double-blindly divided into 2 groups: Group D (n=15) received Dex 0.4 mu g/kg iv administered over 5 min and Group C (n=15) received equal volume of normal saline. Values of BIS, AAI, MAP, HR were recorded every 2 min within 20 min after the administration of the drugs.

RESULTSBefore anesthesia the BIS index was 90 +/- 2 in Group D and 92 +/- 2 in Group C, AAI was 81 +/- 1 in Group D and 78 +/- 1 in Group C. In anesthesia with target controlled infusion of propofol, BIS index showed a significant decrease with the i.v. administration of Dex 0.4 microg/kg, while AAI remained unchanged. In Group C, both of BIS and AAI remained unchanged after saline injection.

CONCLUSIONDuring propofol and remifentanyl anesthesia, after the administration of Dex, BIS value demonstrates a predominant decrease, whereas AAI shows no changes.

Adrenergic alpha-Agonists ; administration & dosage ; Adult ; Androstanols ; administration & dosage ; Anesthetics, Combined ; administration & dosage ; Anesthetics, Intravenous ; administration & dosage ; Dexmedetomidine ; administration & dosage ; pharmacology ; Double-Blind Method ; Evoked Potentials, Auditory ; drug effects ; Female ; Humans ; Infusions, Intravenous ; methods ; Male ; Medetomidine ; pharmacology ; Middle Aged ; Monitoring, Intraoperative ; methods ; Neuromuscular Nondepolarizing Agents ; administration & dosage ; Piperidines ; administration & dosage ; pharmacology ; Propofol ; administration & dosage ; pharmacology ; Thyroidectomy

This study aims to elucidate the mechanisms by which dexmedetomidine alleviates pulmonary edema in rats with acute lung injury induced by lipopolysaccharide (LPS). Male Wistar rats were randomly divided into five groups: normal saline control (NS) group, receiving intravenous 0.9% normal saline (5 mL/kg); LPS group, receiving intravenous LPS (10 mg/kg); small-dose dexmedetomidine (S) group, treated with a small dose of dexmedetomidine (0.5 μg · kg(-1) · h(-1)); medium-dose dexmedetomidine (M) group, treated with a medium dose of dexmedetomidine (2.5 μg · kg(-1) · h(-1)); high-dose dexmedetomidine (H) group, treated with a high dose of dexmedetomidine (5 μg · kg(-1) · h(-1)). The rats were sacrificed 6 h after intravenous injection of LPS or NS, and the lungs were removed for evaluating histological characteristics and determining the lung wet/dry weight ratio (W/D). The levels of tumor necrosis factor-alpha (TNF-&alpha;) and interleukin-1β (IL-1β) in the lung tissues were assessed by enzyme- linked immunosorbent assay (ELISA). The mRNA and protein expression levels of aquaporin-1 (AQP1) and aquaporin-5 (AQP5) were detected by RT-PCR, immunohistochemistry, and Western blotting. The lung tissues from the LPS groups were significantly damaged, which were less pronounced in the H group but not in the small-dose dexmedetomidine group or medium-dose dexmedetomidine group. The W/D and the concentrations of TNF-&alpha; and IL-1β in the pulmonary tissues were increased in the LPS group as compared with those in NS group, which were reduced in the H group but not in S group or M group (P<0.01). The expression of AQP1 and AQP5 was lower in the LPS group than in the NS group, and significantly increased in the H group but not in the S group or M group (P<0.01). Our findings suggest that dexmedetomidine may alleviate pulmonary edema by increasing the expression of AQP-1 and AQP-5.
Acute Lung Injury ; chemically induced ; drug therapy ; genetics ; pathology ; Adrenergic alpha-2 Receptor Agonists ; pharmacology ; Animals ; Aquaporin 1 ; agonists ; genetics ; immunology ; Aquaporin 5 ; agonists ; genetics ; immunology ; Dexmedetomidine ; pharmacology ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Gene Expression Regulation ; Injections, Intravenous ; Interleukin-1beta ; antagonists & inhibitors ; genetics ; immunology ; Lipopolysaccharides ; Lung ; drug effects ; immunology ; pathology ; Male ; Organ Size ; drug effects ; Pulmonary Edema ; chemically induced ; drug therapy ; genetics ; pathology ; Rats ; Rats, Wistar ; Signal Transduction ; Transcription, Genetic ; Tumor Necrosis Factor-alpha ; antagonists & inhibitors ; genetics ; immunology

PURPOSE: To screen for diabetic autonomic neuropathy of the pupil using 0.5% apraclonidine and 0.1% pilocarpine and to evaluate the early diagnostic value of this pharmacologic pupillary test by assessing the relationship between pupillary and cardiovascular autonomic neuropathies. METHODS: A total of 22 diabetic patients were recruited. Baseline pupillary diameter (PD) and the difference in PD between the test eye and the control eye before and after instillation of apraclonidine and pilocarpine were measured. All patients also underwent cardiovascular autonomic function (CAF) testing. RESULTS: Baseline PD in room light correlated with duration of diabetes mellitus (DM, p=0.049) and the presence of DM retinopathy (DMR, p=0.022). Eleven patients (50%) had positive apraclonidine tests, and two patients had positive pilocarpine tests. The patients who had positive pilocarpine tests also had positive apraclonidine tests. Patients who had a positive pupillary test had a significantly higher rate of positive CAF tests (p=0.032). CONCLUSIONS: Pupillary autonomic neuropathy was related to the duration of diabetes and the degree of DMR. There was also a significant correlation between pupillary autonomic neuropathy and cardiovascular autonomic neuropathy (CAN). Also, sympathetic nerve dysfunction occurred prior to parasympathetic dysfunction in this study. A simple pharmacologic pupillary test can help manage complications in diabetic patients because patients with pupillary autonomic dysfunction have an increased risk of CAN.
Adrenergic alpha-Agonists/administration & dosage/diagnostic use ; Adult ; Aged ; Clonidine/administration & dosage/*analogs & derivatives/diagnostic use ; Diabetic Nephropathies/*diagnosis/physiopathology ; Diagnosis, Differential ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Miosis/*chemically induced/physiopathology ; Miotics/administration & dosage/diagnostic use ; Ophthalmic Solutions ; Pilocarpine/administration & dosage/*diagnostic use ; Pupil/drug effects/*physiology ; Reproducibility of Results

The aim of this study is to investigate the effect of isosorbide-5-mononitrate (ISMN) on the electric field stimulation induced sympathetic purinergic vasoconstriction of the rabbit saphenous arterial rings. Isometric vasoconstrictive responses to electric field stimulation and to exogenous noradrenaline and adenosine triphosphate were recorded. We found that the vasoconstrictive responses to electric field stimulation (15 V, 1 ms pulse duration, 2 - 16 Hz) were frequency-dependant in the rabbit saphenous arterial rings, and abolished by tetrodotoxin (0.1 micromol x L(-1)). The alpha1-adrenoceptor antagonist prazosin (1 micromol x L(-1)) did not affect the vascular responses to the electric field stimulation (2 -8 Hz). After a combination treatment with both alpha,beta-meATP (3 micromol x L(-1), desensitizing P2X1 receptors) and prazosin (1 micromol x L(-1)), the vasoconstrictive responses to electric field stimulation were abolished. When the arterial preparation was treated with ISMN (one preparation was exposed to only one concentration of ISMN), ISMN at 0.1 mmol x L(-1) significantly inhibited the vasoconstriction induced by electric stimulation at 8 Hz, 0.3 and 1.0 mmol x L(-1) significantly inhibited the vasoconstrictive responses to electric stimulation at 2 - 16 Hz. The highest concentration of ISMN (1.0 mmol x L(-1)) reduced the vasoconstrictive responses by 46% (2 Hz), 47% (4 Hz), 34% (8 Hz) and 22% (16 Hz), separately. ISMN (0.3 and 1.0 mmol x L(-1)) did not affect the vascular responses to exogenous noradrenaline (0.01-100 micromol x L(-1)) and adenosine triphosphate (1 mmol x L(-1)). It is reasonable to suggest that ISMN inhibits the purinergic vasoconstriction induced by sympathetic nerve stimulation via a prejunctional mechanism.
Adenosine Triphosphate ; analogs & derivatives ; pharmacology ; Adrenergic alpha-Antagonists ; pharmacology ; Animals ; Arteries ; drug effects ; Delayed-Action Preparations ; Electric Stimulation ; Isosorbide Dinitrate ; administration & dosage ; analogs & derivatives ; pharmacology ; Male ; Norepinephrine ; pharmacology ; Prazosin ; pharmacology ; Purinergic P2 Receptor Agonists ; Rabbits ; Receptors, Purinergic P2X ; Vasoconstriction ; drug effects

Spinal gabapentin has been known to show the antinociceptive effect. Although several assumptions have been suggested, mechanisms of action of gabapentin have not been clearly established. The present study was undertaken to examine the action mechanisms of gabapentin at the spinal level. Male SD rats were prepared for intrathecal catheterization. The effect of gabapentin was assessed in the formalin test. After pretreatment with many classes of drugs, changes of effect of gabapentin were examined. General behaviors were also observed. Intrathecal gabapentin produced a suppression of the phase 2 flinching, but not phase 1 in the formalin test. The antinociceptive action of intrathecal gabapentin was reversed by intrathecal NMDA, AMPA, D-serine, CGS 15943, atropine, and naloxone. No antagonism was seen following administration of bicuculline, saclofen, prazosin, yohimbine, mecamylamine, L-leucine, dihydroergocristine, or thapsigargin. Taken together, intrathecal gabapentin attenuated only the facilitated state. At the spinal level, NMDA receptor, AMPA receptor, nonstrychnine site of NMDA receptor, adenosine receptor, muscarinic receptor, and opioid receptor may be involved in the antinociception of gabapentin, but GABA receptor, L-amino acid transporter, adrenergic receptor, nicotinic receptor, serotonin receptor, or calcium may not be involved.
Acetic Acids/administration & dosage ; Acetic Acids/metabolism ; Acetic Acids/pharmacology* ; Adrenergic Antagonists/metabolism ; Adrenergic alpha-Antagonists/metabolism ; Analgesics/administration & dosage ; Analgesics/metabolism ; Analgesics/pharmacology* ; Animals ; Atropine/metabolism ; Dihydroergocristine/metabolism ; Enzyme Inhibitors/metabolism ; Excitatory Amino Acid Agonists/metabolism ; GABA Antagonists/metabolism ; Injections, Spinal ; Leucine/metabolism ; Male ; Mecamylamine/metabolism ; Muscarinic Antagonists/metabolism ; N-Methylaspartate/metabolism ; Naloxone/metabolism ; Narcotic Antagonists/metabolism ; Nicotinic Antagonists/metabolism ; Pain Measurement ; Quinazolines/metabolism ; Rats ; Rats, Sprague-Dawley ; Serine/metabolism ; Spinal Cord/drug effects* ; Thapsigargin/metabolism ; Triazoles/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism