GABA(A) and GABA(C) receptors have contrasting effects on excitability in superior colliculus.
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We have recently found that GABA(C) receptor subunit transcripts are expressed in the superficial layers of rat superior colliculus (SC). In the present study we used immunocytochemistry to demonstrate the presence of GABA(C) receptors in rat SC at protein level. We also investigated in acute rat brain slices the effect of GABA(A) and GABA(C) receptor agonists and antagonists on stimulus-evoked extracellular field potentials in SC. Electrical stimulation of the SC optic layer induced a biphasic, early and late, potential in the adjacent superficial layer. The late component was completely inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione or CoCl(2), indicating that it was generated by postsynaptic activation. Muscimol, a potent GABA(A) and GABA(C) receptor agonist, strongly attenuated this postsynaptic potential at concentrations >10 microM. In contrast, the GABA(C) receptor agonist cis-aminocrotonic acid, as well as muscimol at lower concentrations (0.1-1 microM) increased the postsynaptic potential. This increase was blocked by (1,2,5, 6-tetrahydropyridine-4-yl)methylphosphinic acid, a novel competitive antagonist of GABA(C) receptors. Our findings demonstrate the presence of functional GABA(C) receptors in SC and suggest a disinhibitory role of these receptors in SC neuronal circuitry. (+info)
Effect of epinephrine on lidocaine clearance in vivo: a microdialysis study in humans.
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BACKGROUND: Local anesthetic nerve block prolonged by epinephrine is thought to result from local vasoconstriction and consequent decreased local anesthetic clearance from the injection site. However, no study has yet confirmed this directly in humans by measuring tissue concentrations of local anesthetic over time. In addition, recent studies have shown that the alpha2-adrenergic receptor agonist, clonidine, also prolongs nerve block without altering local anesthetic clearance. Because epinephrine is also an alpha2-adrenergic receptor agonist, it is possible that epinephrine prolongs local anesthetic block by a pharmacodynamic mechanism and not a pharmacokinetic one. This study was designed to address this issue. METHODS: Microdialysis probes were placed adjacent to the superficial peroneal nerve in both feet of eight volunteers. Plain lidocaine (1%) was injected along one peroneal nerve and lidocaine with epinephrine (2.5 microg/ml) was injected along the other nerve in a double-blinded, randomized manner. The concentration of lidocaine in tissue was measured at 5-min intervals, and sensory block and cutaneous blood flow were assessed by laser Doppler at 10-min intervals for 5 h. The resulting data for lidocaine concentration versus time were fit to a two-compartment model using modeling software. RESULTS: Epinephrine prolonged sensory block by decreasing local blood flow and slowing clearance. There was no evidence of a pharmacodynamic effect of epinephrine. CONCLUSION: Although epinephrine activates alpha2-adrenergic receptors, its mechanism for prolonging the duration of local anesthetic block rests on its ability to decrease local anesthetic clearance and not on a pharmacodynamically mediated potentiation of local anesthetic effect. (+info)
BACKGROUND: Spontaneous tremor is relatively common in normothermic patients after operation and has been attributed to many causes. The hypothesis that nonthermoregulatory shivering-like tremor is facilitated by postoperative pain was tested. In addition, the effects of intravenous lidocaine on nonthermoregulatory tremor were evaluated. METHODS: Patients undergoing knee surgery were anesthetized with 2 microg/kg intravenous fentanyl and 0.2 mg/kg etomidate. Anesthesia was maintained with 1.7 +/- 0.8% (mean +/- SD) isoflurane. Intraoperative forced-air heating maintained normothermia The initial 44 patients were randomly allocated to receive an intra-articular injection of 20 ml saline (n = 23) or lidocaine, 1.5% (n = 21). The subsequent 30 patients were randomly allocated to receive an intravenous bolus of 250 microg/kg lidocaine followed by an infusion of 13 microg x kg(-1) x h(-1) lidocaine or an equivalent volume of saline when shivering was observed. Patient-controlled analgesia was provided for all patients: 3.5 mg piritramide, with a lockout interval of 5 min, for an unlimited total dose. Shivering was graded by a blinded investigator using a four-point scale. Pain was assessed by a 100-mm visual analog scale (0 = no pain and 100 = worst pain). The arteriovenous shunt status was evaluated with forearm-minus-fingertip skin-temperature gradients. RESULTS: Morphometric characteristics and hemodynamic responses were similar in the four groups. Core and mean skin temperature remained constant or increased slightly compared with preoperative values, and postoperative skin-temperature gradients were negative (indicating vasodilation) in nearly all patients. After intra-articular injection of saline, pain scores for the first postoperative hour averaged 46 +/- 32 mm (mean +/- SD), and 10 of the 23 (43%) patients shivered. In contrast, the pain scores of patients who received intra-articular lidocaine were significantly reduced to 5 +/- 9 mm and shivering was absent in this group (P < 0.05). In the second portion of the study, neither intravenous lidocaine nor saline reduced the magnitude or duration of nonthermoregulatory tremor or the patients' pain scores. CONCLUSIONS: Intra-articular, but not intravenous, lidocaine reduced surgical pain and prevented nonthermoregulatory shivering. Therefore, these data indicate that postoperative pain facilitates nonthermoregulatory shivering. (+info)
Nitric oxide increases persistent sodium current in rat hippocampal neurons.
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1. The effects of nitric oxide (NO) donors on whole-cell, TTX-sensitive sodium currents and single sodium channels in excised patches were examined in rat hippocampal neurons. The whole-cell sodium current consisted of a large transient component (INa,t) and a smaller, inactivation-resistant, persistent component (INa,p). 2. In acutely dissociated neurons, the amplitude of the whole-cell INa, p increased by 60-80 % within a few minutes of exposure to either of two NO donors, sodium nitroprusside (SNP, 100 microM) or S-nitroso-N-acetyl-DL-penicillamine (SNAP, 100 microM). 3. The amplitude of INa,t was not changed significantly by the same concentrations of SNP and SNAP, indicating that NO had a selective effect on INa,p. 4. Both NO donors significantly increased the mean persistent current in excised inside-out patches from cultured hippocampal neurons. SNP at 10-100 microM increased average mean persistent current at a pipette potential (Vp) of +30 mV from -0.010 +/- 0.014 pA (control) to -2.91 +/- 1.41 pA (n = 10). SNAP at 3-100 microM increased the average mean inward current in six inside-out patches from -0.07 +/- 0.02 to -0.30 +/- 0.08 pA (Vp = +30 mV). 5. The increase in persistent Na+ channel activity recorded in inside-out patches in the presence of SNP or SNAP could be reversed by the reducing agent dithiothreitol (DTT, 2-5 mM) or by lidocaine (1-10 microM). 6. The average mean current recorded in the presence of SNP was 10-fold higher than that elicited by SNAP. The time delay before an increase was observed was shorter with SNP (4.0 +/- 0.8 min, n = 8) than with SNAP (8.4 +/- 1.6 min, n = 7). 7. A component of the SNP molecule added on its own, 5 mM sodium cyanide (NaCN), increased mean current in excised inside-out patches (Vp = +30 mV) from -0.06 +/- 0.04 to -0.58 +/- 0.21 pA (n = 19). This increase in channel activity could be blocked by 10 microM lidocaine and 2-5 mM DTT. 8. These results suggest that NO may directly increase the activity of neuronal persistent Na+ channels, but not transient Na+ channels, through an oxidizing action directly on the channel protein or on a closely associated regulatory protein in the plasma membrane. (+info)
K(+)-induced neurogenic relaxation of rat distal colon.
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Relaxations of segments of rat distal colon were elicited by hypertonic solutions of potassium (K(+); final concentration, 20.8 or 50.8 mM). The initial part of the response to K(+) was antagonized by the nerve blocker tetrodotoxin. This effect could, moreover, be significantly antagonized by apamin (a blocker of K(+) channels), reactive blue 2 (a P(2y)-purinoceptor antagonist), N(G)-nitro-L-arginine (an inhibitor of NO synthase), 1H-[1,2,4]- oxadiazolo[4,3-a]quinoxaline-1-one (ODQ; an inhibitor of soluble guanylyl cyclase), or N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89; an inhibitor of cAMP-dependent protein kinase). Sodium nitroprusside (a donor of NO) and vasoactive intestinal peptide (VIP) both relaxed the tissues. The response to sodium nitroprusside was abolished by ODQ and unaffected by H-89, and that to VIP was partially inhibited by VIP(10-28) (a VIP receptor antagonist), ODQ, or H-89. When combining reactive blue 2 and N(G)-nitro-L-arginine, the response to 50.8 mM K(+) was reduced by approximately 70% and was abolished by the concomitant administration of these antagonists and VIP(10-28). ATP, NO, and VIP may, thus, be inhibitory neurotransmitters in rat distal colon. (+info)
Pharmacological isolation of the synaptic and nonsynaptic components of the GABA-mediated biphasic response in rat CA1 hippocampal pyramidal cells.
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High-frequency stimulation (HFS) applied to stratum radiatum of a rat hippocampal slice in the presence of ionotropic glutamate receptor antagonists evokes a biphasic GABA(A) receptor-dependent response in CA1 pyramidal neurons, with a brief hyperpolarizing IPSP (hIPSP) followed by a long-lasting depolarization. We show now that it is possible to pharmacologically separate the hIPSP and late depolarization from one another. In neurons intracellularly perfused for 1-2 hr with F(-) as the major anion and no ATP, the hIPSP (and the corresponding current, hIPSC) evoked by HFS was blocked, whereas neither the late depolarization nor its underlying current was attenuated. In contrast, internal perfusion with a high concentration (5 mM) of the impermeant lidocaine derivative QX-314 selectively abolished the depolarizing component of the biphasic response and also strongly reduced depolarizations evoked by extracellular microinjection of K(+). Bath application of quinine (0. 2-0.5 mM) or quinidine (0.1 mM) resulted in a pronounced inhibition of the HFS-induced extracellular K(+) concentration ([K(+)](o)) transient but not of the bicarbonate-dependent alkaline shift in extracellular pH. The attenuation of the [K(+)](o) transient was closely paralleled by a suppression of the HFS-evoked depolarization but not of the hIPSP. Quini(di)ne did not affect depolarizations induced by exogenous K(+) either. These data provide direct pharmacological evidence for the view that the HFS-induced biphasic response of the pyramidal neuron is composed of mechanistically distinct components: a direct GABA(A) receptor-mediated phase, which is followed by a slow, nonsynaptic [K(+)](o)-mediated depolarization. The bicarbonate-dependent, activity-induced [K(+)](o) transient can be blocked by quini(di)ne, whereas its depolarizing action in the pyramidal neuron is inhibited by internal QX-314. The presence of fundamentally distinct components in GABA(A) receptor-mediated actions evoked by HFS calls for further investigations of their functional role(s) in standard experimental maneuvers, such as those used in studies of synaptic plasticity and induction of gamma oscillations. (+info)
Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes depends on alpha (hH1 vs. rSkM1) and beta 1 subunits.
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OBJECTIVE: The affinity of lidocaine for the alpha-subunit of the Na channel has been reported to be greater for heart than for non-heart alpha-subunits, and also to be no different. Lidocaine block has a complex voltage dependence caused by a higher affinity for the inactivated state over the resting state. Inactivation kinetics, however, depend upon the alpha-subunit isoform and the presence of the auxiliary beta 1-subunit and will affect measures of block. METHODS: We studied the voltage dependence of lidocaine block of Na currents by a two microelectrode voltage clamp in oocytes injected with RNA for the Na channel alpha-subunits of human heart (hH1a) or a rat skeletal muscle (rSkM1) alone, or coexpressed with the beta 1-subunit. RESULTS: The midpoints of availability for a 25-s conditioning potential in control solutions were -65 mV for rSkM1, -50 for rSkM1 + beta 1, -78 mV for hH1a and -76 for hH1a + beta 1. The Kd of tonic lidocaine block was measured at -90, -100, -110, -120 and -130 mV in the same oocytes. The apparent Kd for both isoforms +/- beta 1 became greater with more negative holding potentials, but tended to reach different plateaus at -130 mV (Kd = 2128 microM for rSkM1, 1760 microM for rSkM1 + beta 1, 433 for hH1a, and 887 microM for hH1a + beta 1). Inactivated state affinities, assessed by fitting the shift in the Boltzmann midpoint of the availability relationship to the modulated receptor model, were 4 microM for rSkM1, 1 microM for rSkM1 + beta 1, 7 microM for hH1a and 9 microM for hH1a + beta 1. CONCLUSION: The heart Na channel alpha-subunits expressed in oocytes have an intrinsically higher rest state affinity for lidocaine compared to rSkM1 after the voltage- and state dependence of block are considered. Coexpression with beta 1 modestly increased the rest affinity of lidocaine for rSkM1, but had the opposite effect for hH1a. (+info)
Steroid injection for heel pain: evidence of short-term effectiveness. A randomized controlled trial.
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OBJECTIVES: To compare the effectiveness of a steroid injection (25 mg/ml prednisolone acetate) with a local anaesthetic control in the treatment of heel pain and to determine any advantage for patients' comfort of using a posterior tibial nerve block to anesthetize the heel prior to infiltration. METHODS: A double-blind randomized controlled trial using a 2 x 2 design in a hospital-based rheumatology clinic. Subjects comprised 106 patients with heel pain referred by general practitioners and other rheumatologists working in Camden and Islington Health Authority. MAIN OUTCOME MEASURES: heel pain reduction at 1, 3 and 6 months, and patient comfort at the time of injection. All outcomes were measured using a 10 cm visual analogue scale. RESULTS: A statistically significant reduction in pain was detected at 1 month (P=0.02) in favour of steroid injection, but thereafter no differences could be detected. Patient comfort was not significantly affected by anaesthesia of the heel (P=0.5). CONCLUSIONS: A steroid injection can provide relief from heel pain in the short term. There appears to be no increase in patient comfort from anaesthetizing the heel prior to infiltration. (+info)