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PubMed2001

Diminished skin blood flow in Type I diabetes: evidence for non-endothelium-dependent dysfunction.

The purpose of this study was to quantify the extent to which skin blood flow (SBF) responses to application of endothelium-dependent and -independent vasodilating agents differ between Type I diabetic patients and healthy subjects. Patients and matched controls were studied after an overnight fast. SBF was determined with laser Doppler perfusion imaging before and after iontophoresis of acetylcholine (Ach; endothelium-dependent) and sodium nitroprusside (SNP; endothelium-independent). Basal SBF did not differ significantly between groups. Iontophoresis of ACh and SNP increased SBF 20-fold in controls. In the patients, the increases in SBF following iontophoresis of ACh and SNP were reduced by 18% and 19%, respectively, versus controls (P<0.05 for both). These data demonstrate that Type I diabetic patients have similar diminished SBF responses to iontophoresis of ACh and SNP, which suggests that non-endothelial-dependent factors are primarily responsible for the diminished SBF responses.

Acetylcholine↗

PubMed1993

[Reversal by the calcium ion of the pain threshold elevated by calcium channel blockers].

We investigated calcium ion effects on pain thresholds by iontophoresis in healthy adult volunteers. The pain thresholds were measured by the pain thermometer to evaluate the effect of iontophoresis. At first, one of calcium channel blockers (nicardipine, verapamil or diltiazem) was administered by iontophoresis with 1.0 mA for 10 minutes. Then, next to calcium channel blockers, calcium chloride or saline was locally administered after the elevation of pain threshold had been recognized and the pain threshold had been measured again. Calcium ion decreased the elevation of pain threshold significantly, but saline had no effect. These results suggest that not only sodium channel but also calcium channel influences pain mechanism during iontophoresis.

Adult↗

PubMed1990

Organization and actions of the noradrenergic input to the hamster's superior colliculus.

Immunocytochemistry using antisera directed against dopamine-beta-hydroxylase (DBH) was used to determine the organization of the noradrenergic (NE) input to the hamster's superior colliculus (SC). Immunocytochemistry for DBH was combined with retrograde transport of fluorogold (FG) to determine the sources of NE input to SC. Microiontophoretic techniques were used together with extracellular single unit recording and receptive field mapping techniques to determine the manner in which NE influenced the responses of individual SC neurons. The hamster's SC contained numerous DBH-positive fibers but no immunopositive cells. These fibers formed a plexus that was most dense in the lower stratum griseum superficiale (SGS). The density of DBH-positive fibers was very low in the stratum opticum (SO) and increased in density in the stratum griseum intermediale (SGI) and the other deep layers. When FG injections into the SC were combined with immunocytochemical detection of DBH, double-labeled cells were observed in the contralateral locus ceruleus. DBH-positive neurons were observed in several other portions of the mesencephalon and pons, but none of these were labelled with FG. The effects of NE iontophoresis were assessed for a total of 135 SC neurons. In 74% (N = 100), NE reduced spontaneous and/or stimulus evoked activity. In 3% (N = 4 cells), NE increased activity, and in 23% (N = 31 cells) it had no effect. These percentages were essentially the same for superficial layer visual cells and somatosensory neurons in the deep laminae. The effect of NE iontophoresis upon signal to noise ratios was assessed for 46 visual and 56 somatosensory neurons. For 54% (N = 25) of the visual cells and 16% (N = 9) of the somatosensory cells, NE iontophoresis decreased signal to noise ratios. For 13% (N = 6) of the visual cells and 21% (N = 12) of the somatosensory cells, NE iontophoresis increased signal to noise ratios. The effects of NE on the responsivity of SC neurons were antagonized by propranolol (86% of the 21 cells tested), sotalol (67% of the six cells tested), and atenolol (effective in the single cell tested). All these agents are beta-adrenergic antagonists. The single alpha-adrenergic antagonist that we evaluated, corynanthine, potentiated the effects of NE on the responsivity of the two SC neurons that we tested.

Action Potentials↗

PubMed2003

GABA(A) and GABA(B) receptors mediated inhibition affect the pattern adaptation of relay cells in the dorsal lateral geniculate nucleus (LGNd) of cats.

Pattern adaptation is very important for visual function, while the mechanisms that mediate pattern adaptation, especially in the dorsal lateral geniculate nucleus (LGNd), are still unclear. Iontophoresis of the antagonists and agonists of GABA receptors were employed to separately investigate the contribution of GABA(A) and GABA(B) receptors to pattern adaptation of LGNd cells. When GABA(A) receptors were blocked by bicuculline both the response amplitude of LGNd cells and the degree of adaptation increased significantly. Many neurons showing no pattern adaptation under the normal condition became adapted to a prolonged stimulus. Moreover, the proportion of cells showing adaptation doubled (from 40 to 88%). The mean adaptation index (AI, adapted response amplitude/original response amplitude) was 0.82 during bicuculline application, compared with 0.92 under the control condition. In additional, iontophoresis of baclofen, a selective GABA(B) receptor agonist, decreased the mean response amplitude to grating stimuli to 53% of normal. Nearly half of the neurons increased their adaptation index following baclofen administration and the mean AI increased from 0.89 to 1.01. Iontophoresis of GABA(B) receptor antagonist (CGP35348) could abolish this effect, though it had no significant effect on visual response amplitude and pattern adaptation itself. Iontophoresis of another GABA(B) receptor antagonist, 2-OH-saclofen, also had no significant effect on visual response amplitude and pattern adaptation. These results suggest that both GABA(A) receptors and GABA(B) receptors modulate the pattern adaptation of LGNd cells and are involved in synaptic plasticity.

Action Potentials↗

PubMed2002

Serotonergic modulation of respiratory motoneurons and interneurons in brainstem slices of perinatal rats.

Respiration-related membrane potential fluctuations were recorded in hypoglossal (XII) motoneurons and pre-Bötzinger complex (pre-BötC) interneurons in medullary slices from perinatal rats. Bath application of serotonin (5-HT) evoked a ketanserine-sensitive depolarization (approximately 11 mV) and tonic spike discharge in XII motoneurons, whereas pre-BötC neurons responded with a <6 mV depolarization and no tonic discharge. The membrane effects were accompanied by an increase in respiratory frequency by up to 260% in 64% of preparations. A frequency decrease leading to block of respiratory activity could also occur (20%) as well as an initial acceleration that turned into a frequency depression (16%). In contrast, iontophoresis of 5-HT into the pre-BötC exclusively increased respiratory frequency by 30-220%, whereas iontophoresis into the XII nucleus did not change respiratory frequency but induced tonic nerve discharge. The effects of local iontophoretic administration of 5-HT on membrane properties of XII and pre-BötC cells were very similar to those upon bath application. Bath application and iontophoresis of the 5-HT2 receptor agonist -methyl-hydroxytryptamine mimicked the effects of 5-HT. Bath application of the 5-HT1A receptor agonist 8-hydroxydipropylaminotetralin hydrobromide did not affect XII nerve bursting or pre-BötC neurons. Iontophoresis of 8-hydroxydipropylaminotetralin hydrobromide had almost no effect on respiratory frequency and induced in the interneurons either a depolarization or hyperpolarization (<5 mV) which was blocked by the 5-HT1A receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)N-2-pyridinylcyclohexane carboxamide. In conclusion, 5-HT-evoked tonic excitation of respiratory XII motoneurons is mediated by postsynaptic 5-HT2 receptors. The excitatory effects on respiratory rhythm are also primarily attributable to postsynaptic 5-HT2 receptors of pre-BötC neurons. Additional modulatory effects on the interneurons appear to be mediated by postsynaptic 5-HT1A receptors.

Action Potentials↗

PubMed2000

Correlations between serotonin level and single-cell firing in the rat's nucleus raphe magnus.

The relation between serotonin release and electrical activity was examined in the nucleus raphe magnus of rats anesthetized with pentobarbital. Serotonin levels were monitored through a carbon-fiber microelectrode by fast cyclic voltammetry (usually at 1 Hz). Single-cell firing was recorded through the same microelectrode, except during the voltammetry waveform and associated electrical artifact (totaling about 30 ms). Multi-barrel micropipettes incorporating the voltammetry electrode were used for iontophoresis of drugs. Cells were inhibited, excited or unaffected by noxious mechanical skin stimulation. These were respectively designated as off(M) cells, on(M) cells and neutral(M) cells, M denoting mechanical. During 3 min of pinching, serotonin slowly rose near seven of 14 on(M) cells and 26 of 46 off(M) cells; it fell near two off(M) cells; it was unchanged near all other cells, including six neutral(M) cells. On a finer spatiotemporal scale, near four of seven on(M) cells, 10 of 14 off(M) cells and 0 of four neutral(M) cells, average serotonin levels fell significantly within +/- 100 ms of spontaneous spikes. Lower serotonin may have caused the higher spike probability; the converse is theoretically unlikely, since delays between release and detection are estimated to exceed 100 ms. Increased serotonin and decreased firing were always seen following iontophoresis or intravenous injection (1 mg/kg) of the serotonin re-uptake inhibitor clomipramine (n = 7). Iontophoresis of +/- propranolol, whose serotonergic actions include antagonism and partial agonism at 5-HT1 receptors, also increased serotonin and decreased firing (n=4). Methiothepin (intravenous, 1 mg/kg), whose serotonergic actions include 5-HT1 and 5-HT2 antagonism, typically raised serotonin levels (four of five cells) and always blocked inhibition by clomipramine (n = 3). Iontophoresis of glutamate always lowered serotonin and increased firing (n = 4). Since serotonin levels and firing were usually inversely correlated, except near on(M) cells during pinch, we propose that serotonin is released from terminals of incoming nociceptive afferents. Prior neuroanatomical knowledge favors a midbrain origin for these afferents, while some of the drug findings suggest that their terminals possess inhibitory serotonergic autoreceptors, possibly of 5-HT1b subtype. The released serotonin could contribute to the inhibition of off(M) cells and excitation of on(M) cells by noxious stimulation, since inhibitory 5-HT1a receptors and excitatory 5-HT2 receptors, respectively, have previously been shown to dominate their serotonergic responses.

Animals↗

PubMed2001

Vascular and nociceptive effects of localized prolonged sympathetic blockade in human skin.

Supersensitivity to noradrenaline contributes to certain vascular disorders (e.g., hypertension) and chronic neuropathic pain conditions (e.g., complex regional pain syndrome). We aimed to develop a procedure for inducing adrenergic supersensitivity that could be used to investigate the role of catecholamines in these clinical conditions. In the first study, three doses of guanethidine were administered by iontophoresis to separate small patches of skin in the forearm of healthy human volunteers. Four to five hours later. the vasoconstrictor response to the adrenergic releasing agent tyramine was inhibited in a dose-dependent manner by iontophoretic pretreatment with guanethidine, indicating that guanethidine had depleted endogenous adrenergic stores. In a second study, guanethidine and saline were administered by iontophoresis four times over approximately 2 weeks at separate sites in the forearm. One to two days after the final pretreatment, vasoconstriction to the iontophoresis of a weak dose of noradrenaline was enhanced at sites pretreated with guanethidine. To investigate the effect of guanethidine pretreatment on thermal hyperalgesia. the experimental sites were sensitized to heat by the topical application of 0.6% capsaicin. Both before and after the application of capsaicin, the heat-pain threshold and heat-pain ratings to suprathreshold stimulation were similar at sites pretreated for 2 weeks with guanethidine or saline. However, after the iontophoresis of noradrenaline, thermal hyperalgesia was greater at the guanethidine-pretreated site than the saline pretreated site. These observations indicate that prolonged depletion of adrenergic stores by guanethidine induces adrenergic supersensitivity in cutaneous vessels, and that adrenergic supersensitivity enhances thermal hyperalgesia in the presence of noradrenaline.

Adult↗

PubMed2001

Repeated local administration of noradrenaline or saline inhibits thermal hyperalgesia in pain-sensitized human skin.

AIMS: Noradrenaline increases thermal hyperalgesia in skin sensitized to heat by the topical application of capsaicin. The aim of this study was to determine whether desensitization to the hyperalgesic effects of noradrenaline would develop after repeated local administrations of noradrenaline in the skin of the forearm. METHODS: Noradrenaline and saline were administered to the forearm by iontophoresis (200 microA, 2 min, over a surface area of 3.1 cm(2)) two times per day for 4-10 days in 19 healthy subjects. The adequacy of the desensitization procedure was evaluated by measuring noradrenaline-induced vasoconstriction with laser Doppler fluxmetry. Thresholds and pain ratings to heat were then investigated at treated and control sites before and after the topical application of capsaicin, and after the iontophoresis of noradrenaline. RESULTS: At previously untreated sites blood flow was 49 +/- 14% (+/- 95% confidence intervals) lower than flow at reference sites after the iontophoresis of noradrenaline. Vascular signs of adrenergic desensitization developed after 4-5 days of repeated local administration of noradrenaline in the majority of subjects. In those whose vessels constricted after the acute administration of noradrenaline, the adrenergic response averaged 23 +/- 15% at the desensitized site compared with 61 +/- 9% at previously untreated sites (P < 0.001). However, similar signs developed after repeated iontophoreses of saline (adrenergic response 7 +/- 16% compared with 58 +/- 15% at previously untreated sites, P < 0.001). Both the noradrenaline and saline treatments inhibited thermal hyperalgesia after the topical application of capsaicin. Heat-pain thresholds averaged 43.2 +/- 2.5 degrees C and 43.0 +/- 2.3 degrees C at the noradrenaline and saline pretreated sites compared with 41.4 +/- 2.7 degrees C at the control site (P < 0.05 and P < 0.06, respectively). On a 0-10 scale, heat-pain ratings to a 7 s, 45 degrees C stimulus averaged 3.8 +/- 1.6 and 3.5 +/- 1.7 at the noradrenaline and saline pretreated sites compared with 5.3 +/- 1.6 at the control site (P < 0.05). After the iontophoresis of noradrenaline heat-pain ratings increased 1.6 +/- 1.4 at the site pretreated with saline (P < 0.05) compared with only 0.4 +/- 1.0 at the site pretreated with noradrenaline (not significant), consistent with local adrenergic desensitization. CONCLUSIONS: We conclude that repeated iontophoreses of noradrenaline or saline inhibit vasoconstriction to noradrenaline, and also inhibit increases in thermal hyperalgesia evoked by capsaicin. The release of endogenous stores of noradrenaline by iontophoretic currents might contribute to these effects.

Administration, Cutaneous↗

PubMed1998

Differences in foot and forearm skin microcirculation in diabetic patients with and without neuropathy.

OBJECTIVE: We have compared the hyperemic response to heat and the endothelium-dependent and endothelium-independent vasodilatation between the dorsum of the foot and the forearm in diabetic neuropathic and non-neuropathic patients and healthy control subjects. RESEARCH DESIGN AND METHODS: We studied the cutaneous microcirculation in the forearm and foot in 15 diabetic patients with neuropathy, in 14 diabetic patients without neuropathy, and in 15 control subjects matched for age, sex, BMI, and in the case of diabetic patients, for the duration of diabetes. Patients with peripheral vascular disease and/or renal impairment were excluded. The cutaneous microcirculation of the dorsum of the foot and the flexor aspect of the forearm was tested in all subjects. Single-point laser Doppler was employed to measure the maximal hyperemic response to heating of the skin to 44 degrees C and laser Doppler imaging scanner was used to evaluate the response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent response) and 1% sodium nitroprusside (NaNP) (endothelium-independent response). RESULTS: The transcutaneous oxygen tension was lower in the neuropathic group at both foot and forearm level, while the maximal hyperemic response to heat was similar at the foot and forearm level in all three groups. The endothelium-dependent vasodilation (percent increase over baseline) was lower in the foot compared to the forearm in the neuropathic group (23 +/- 4 vs. 55 +/- 10 [mean +/- SEM]; P < 0.01)], the non-neuropathic group (33 +/- 6 vs. 88 +/- 14; P < 0.01), and the control subjects (43 +/- 6 vs. 93 +/- 13; P < 0.001). Similar results were observed during the iontophoresis of NaNP (P < 0.05). No differences were found among the three groups when the ratio of the forearm:foot response was calculated for both the endothelium-dependent (neuropathic group, 2.25 +/- 0.24; non-neuropathic group, 2.55 +/- 0.35; and control subjects, 2.11 +/- 0.26; P = NS) and endothelium-independent vasodilation (neuropathic group, 1.54 +/- 0.27; non-neuropathic group, 2.08 +/- 0.33; and control subjects, 2.77 +/- 1.03; P = NS). The vasodilatory response, which is related to the C nociceptive fiber action, was reduced at the foot level during iontophoresis of Ach in the neuropathic group. In contrast, no difference was found during the iontophoresis of NaNP at the foot and forearm level and of Ach at the forearm level among all three groups. CONCLUSIONS: In healthy subjects, the endothelial-dependent and endothelial-independent vasodilatation is lower at the foot level when compared to the forearm, and a generalized impairment of the microcirculation in diabetic patients with neuropathy preserves this forearm-foot gradient. These changes may be a contributing factor for the early involvement of the foot with neuropathy when compared to the forearm.

Adult↗

PubMed1995

Importance of dermal blood supply and epidermis on the transdermal iontophoretic delivery of monovalent cations.

The effect of dermal blood flow on the transdermal iontophoresis of five monovalent cationic solutes has been investigated using an in vivo rat model. The iontophoretic flux of solutes from topical application sites was shown, using anesthetized and sacrificed rats, to be independent of the dermal blood supply. The presence of a viable blood supply significantly affected the extent of penetration of solutes into deeper underlying tissues during iontophoresis. Higher tissue concentrations of solutes were found in the upper tissue layers of sacrificed rats, with no blood supply, compared to those in anesthetized rats. In all animals the highest concentration of solute after 2 h iontophoresis was found in the epidermis. Iontophoretic application of solutes to skin with the epidermis removed resulted in significantly lower fluxes than from sites where the skin was intact. These findings suggest that local blood flow determines systemic and underlying tissue solute absorption but not epidermal penetration fluxes during iontophoretic delivery. Finally, the dependence of iontophoretic transport of a solute on the solute's size in vivo was similar to relationships previously reported for excised human skin studies.

Administration, Cutaneous↗

PubMed2001

Facilitating laser Doppler measurements of cutaneous adrenergic vasoconstriction: a comparison of methods.

Detecting vasoconstriction in the skin of the human forearm is often difficult because cutaneous perfusion is usually low, even in the absence of vasoconstrictive agents. However, flow through "vasoconstricted" skin can be detected by increasing the background skin blood flow. The aim of the current study was to evaluate local warming and postocdusive reactive hyperemia as techniques for increasing background flow to facilitate laser Doppler measurements of cutaneous vasoconstriction in the forearm. Noradrenaline introduced by iontophoresis into the forearm of healthy volunteers initially reduced the peak hyperemic response (mean decrease in hyperemia 21 +/- 7%, p <0.01), compared with a saline control. However, vasoconstriction was unrelated to the dose of noradrenaline and was not detectable when the test was repeated, possibly because the peak of the normal hyperemic response decreased with repeated occlusions. When the forearm was warmed to 42 degrees C, noradrenaline introduced by iontophoresis produced dose-dependent vasoconstriction relative to saline control sites and skin not having undergone iontophoresis (greatest mean decrease 64 +/- 7%, p <0.001). Therefore, local warming is recommended over reactive hyperemia for facilitating laser Doppler recordings of cutaneous vasoconstriction in the human forearm.

Adolescent↗

PubMed1999

The local effects of systemic digoxin on the cutaneous microcirculation.

OBJECTIVE: The present study was designed to explore whether digoxin modifies cutaneous vascular responses to an endothelium-dependent vasodilator (acetylcholine) or to the vasoconstrictor norepinephrine. METHODS: In a double-blind cross-over study 12 healthy subjects received digoxin 0.25 mg twice daily (after adequate loading doses) or placebo for a total of 11 days. Dose-response curves to iontophoresis of acetylcholine or norepinephrine were constructed at day 11. Laser Doppler flux (LDF) was measured at the same sites. Mean arterial pressure (MAP) was measured non-invasively and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). RESULTS: Serum concentrations of digoxin were within the therapeutic range [1.3 (0.5) ng x ml(-1); mean with (SD)]. Blood pressure and heart rate were significantly lower during supine rest under digoxin treatment [mean with (SD); minute 10 to 70 of supine rest; systolic blood pressure: 121 (11) mmHg (placebo) vs 116 (11) mmHg (digoxin); P = 0.001; diastolic blood pressure: 63 (6) mmHg vs 58 (8) mmHg; P = 0.007; heart rate: 60 (10) beats x min(-1) vs 54 (8) beats x min(-1); P = 0.001]. Digoxin also caused significantly higher baseline CVC [169 (25) Perfusion Units (PU) x mmHg(-1) (digoxin) vs 109 (14) PU x mmHg(-1)(placebo); P = 0.013] and significantly increased the vasoconstriction to norepinephrine iontophoresis. Acetylcholine iontophoresis was unaltered by digoxin treatment. CONCLUSIONS: Digoxin does not modify the cutaneous vascular response to an administered endothelium-dependent vasodilator. It reduces resting heart rate, blood pressure and baseline cutaneous blood flow and augments the vasoconstrictive effect of exogenous norepinephrine. The findings do not support the hypothesis that digoxin lowers diastolic blood pressure through a direct action on blood vessels.

Acetylcholine↗

PubMed2005

Compartmental modeling of transdermal iontophoretic transport II: in vivo model derivation and application.

PURPOSE: This study was aimed to develop a family of compartmental models to describe in a strictly quantitative manner the transdermal iontophoretic transport of drugs in vivo. The new models are based on previously proposed compartmental models for the transport in vitro. METHODS: The novel in vivo model considers two separate models to describe the input into the systemic circulation: a) constant input and b) time-variant input. Analogous to the in vitro models, the in vivo models contain four parameters: 1) kinetic lag time (tL), 2) steady-state flux during iontophoresis (JSS), 3) skin release rate constant (KR), and 4) passive flux in the post-iontophoretic period (Jpas). The elimination from the systemic circulation is described by a) the one-compartment and b) the two-compartment pharmacokinetic models. The models were applied to characterize the observed plasma concentration vs. time data following single-dose iontophoretic delivery of growth hormone-releasing factor (GRF) and R-apomorphine. Moreover, the models were also used to simulate the observed plasma concentration vs. time profiles following a two-dose transdermal iontophoretic administration of alniditan. RESULTS: The time-variant input models were superior to the constant input models and appropriately converged to the observed data of GRF and R-apomorphine allowing the estimation of JSS, KR, and Jpas. In most cases, the values of tL were negligible. The estimated JSS and the in vivo flux profiles of GRF and R-apomorphine were similar to those obtained using the deconvolution method. The two-dose iontophoretic transport of alniditan was properly simulated using the proposed time-variant input model indicating the utility of the model to predict and to simulate the drug transport by a multiple-dose iontophoresis. Moreover, the use of the compartmental modeling approach to derive an in vitro-in vivo correlation for R-apomorphine was demonstrated. This approach was also used to identify the optimum in vitro model that closely mimics the in vivo iontophoretic transport of R-apomorphine. CONCLUSIONS: The developed in vivo models demonstrate their consistency and capability to describe the in vivo iontophoretic drug transport. This compartmental modeling approach provides a scientific basis to examine in vitro-in vivo correlations of drug transport by iontophoresis.

Administration, Cutaneous↗

PubMed1978

Effects of acetylcholine and cyclic GMP on input resistance of cortical neurons in awake cats.

The effects on input resistance (Rm) of extracellular iontophoresis of acetylcholine (ACh) and of intracellular iontophoresis of cyclic GMP (cGMP) were studied in neurons of the coronal-pericruciate cortex of awake cats. Control studies were also conducted including iontophoresis of saline extracellularly and 5'-GMP intracellularly. (1) Substantial increases in Rm occurred in approximately half the neurons given ACh or cGMP. (2) In the absence of associated repetitive spike discharge induced by intracellular injection of depolarizing current pulses during iontophoretic applications, the increases in Rm were transient occurring in less than 30 sec and lasting 4--5 min. (3) With associated current-induced spike discharge, the increases in Rm persisted for as long as the neurons could be held -- up to 1.5 h maximally. (4) Rm was not increased if saline was substituted for ACh, if 5'-GMP was substituted for cGMP, or if the neuron was only discharged repeatedly. (5) The magnitude and time course of both transient and persistent increases in Rm were comparable between cells given ACh or cGMP and whether action potentials and resting potentials were greater than or equal to 40 mV (average 47 mV)* or were less.

Acetylcholine↗

PubMed1993

Serotonergic influence from nucleus raphe obscurus on neurones in the periaqueductal grey matter in the rat.

In rats anaesthetised with urethane, iontophoretic application of 5-hydroxytryptamine (5-HT, 5-70 nA) produced changes in ongoing activity of 41/44 neurones in the periaqueductal grey matter (PAG). The majority (85%) of responsive cells were inhibited and 15% were excited. The inhibitions were mimicked in 5/7 cells by iontophoresis of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 10-30 nA) whilst excitation was produced in 3/5 cells by iontophoresis of the 5-HT2 agonist alpha-methyl-5-HT (10-30 nA). Selective activation of neuronal perikarya in nucleus raphe obscurus (NRO) by microinjection of 50-100 nl D,L-homocysteic acid (DLH) inhibited ongoing activity of 25/31 neurones tested in the PAG for periods of 30-580 s, mean 183.5 s. The duration of the inhibition was potentiated by between 36 and 300% during iontophoresis of the 5-HT re-uptake blocker paroxetine (1-25 nA, 6/6 cells). The results indicate that there is an extensive inhibitory serotonergic input to the PAG which originates, at least in part, from NRO.

Animals↗

PubMed1987

The nucleoside-transport inhibitor soluflazine (R 64 719) increases the effects of adenosine in the guinea-pig hippocampal slice and is antagonized by adenosine deaminase.

Field EPSP slope and population spike (PS) amplitude were measured in the CA1 pyramidal cell region after double-pulse stimulation of the striatum radiatum in hippocampal slices of guinea-pig. Iontophoresis of adenosine reduced the EPSP slope to 77.9 +/- 5.0% (mean +/- S.E.M.) and PS amplitude to 32.9 +/- 9.7% of the control values. Recovery was 98.7 +/- 3% for the EPSP and 82.9 +/- 7.0% for the PS 1.5 min after iontophoresis was stopped. In the presence of soluflazine 10(-6) M the effects of adenosine iontophoresis on the PS amplitude were significantly increased and the recovery of the EPSP and PS was significantly delayed. Soluflazine perfusion alone gradually decreased EPSP slope and PS amplitude as with adenosine. The reductions in EPSP slope and PS amplitude produced by soluflazine were antagonized by adenosine deaminase. An increase in EPSP slope and PS amplitude was seen when adenosine deaminase was given first. This increase was not reduced by exposure to soluflazine. These results are compatible with the hypothesis that soluflazine acts as a nucleoside transport inhibitor in the CNS, where it may increase the extracellular concentration of adenosine.

Adenosine↗

PubMed1983

A comparison of the release of substance P and some synthetic analogues from micropipettes by microiontophoresis or pressure.

The release of substance P (SP) and two analogues by iontophoresis or pressure from microelectrodes was compared. Substance P was released linearly by iontophoresis from electrodes while no release of the analogues was detected. [N-methylphenylalanine8, N-methylglycine9-] SP5-11 (DiMeC7) and [methyl-2-aminoethyl]11 SP (SP-DAE) were released from electrodes by pressure ejection with linear relationships in all cases between pressure and the amounts released. Under the tested experimental conditions, release of substance P by iontophoresis was between 2 and 3 orders of magnitude less than that by pressure over a given time. The release of substance P and the uncharged analogue DiMeC7 by pressure was very similar while release of SP-DAE was one order of magnitude less.

Electrophoresis↗

PubMed1987

Effects of acyclovir therapy during simultaneous reactivation of latent HSV-1 in rabbits.

Acyclovir (ACV) therapy with a simultaneous reactivation of latent HSV-1 was evaluated in HSV-1 infected rabbit eyes. When the latently infected rabbits received epinephrine iontophoresis into corneas without ACV therapy 100% of eyes shed virus into tear film. The shedding was initiated on the second day of the epinephrine iontophoresis and lasted for an average of 4.6 days. When the rabbits received ACV (60 mg/kg body weight) intravenously once daily and topically (5% ACV ointment) twice daily for 6 consecutive days while a 0.01% epinephrine solution was iontophoresed into cornea for the first 3 consecutive days, 33% (2/6) of eyes showed detectable HSV-1 in the tear film only after terminating the ACV therapy, and the duration of shedding was for only one day. The average quantity of virus detectable in the tear film was decreased 14-fold in the latter group compared to the epinephrine iontophoresis group without ACV therapy. Four days after the last ACV therapy the titer of HSV-1 in the cell-free homogenates of the trigeminal and superior cervical ganglia was determined. For the epinephrine iontophoresed group, 67% of ganglia (8/12) were HSV-1 positive, while only 33% (4/12) of the ganglia from the combined treatment group were HSV-1 positive. The difference was statistically significant (p = 0.034). Furthermore, the titer of virus detectable in the cell-free homogenates of the virus-positive ganglia from the combined treatment group was less than that from the ganglia of the epinephrine iontophoresed group or untreated group. This suggests a reduction in the total number of latent foci for the combined treatment group.

Acyclovir↗