Depressed Reflexes Research Articles

Electrophysiological evidence for an antinociceptive effect of ketamine in the rat spinal cord.

The dissociative anesthetic ketamine also has antinociceptive effects. The mechanism and the site of action of such effect of ketamine have been, however, elusive and controversial. The present study was conducted to examine the effect of systemically administered ketamine on spinal nociceptive transmission. We investigated and compared the effects of ketamine (0.25-8 mg/kg) on the hamstring flexor reflex in intact, lightly anesthetized rats and spinally transected rats. The opioid receptor antagonist naloxone was used to examine the involvement of opioid receptors in the actions of ketamine. Finally, the effects of ketamine on dorsal horn neuronal activity to electrical stimulation of peripheral nerves were also studied. Ketamine caused similar dose-dependent depression of the hamstring flexor reflex recorded from spinally intact rats and from spinalized rats. Even the highest dose of ketamine failed to influence the monosynaptic reflex. The depressive effect of ketamine on the flexor reflex was not reversed by naloxone. Ketamine i.v. also exerted a relatively selective inhibition of the responses of dorsal horn wide-dynamic-range neurons to C-fiber input of electrical stimulation of the plantar nerve. Our present results support the notion that ketamine can exert a direct antinociceptive effect in rat spinal cord. Moreover, the data indicated that the spinal antinociceptive effect of ketamine does not involve naloxone-sensitive opioidergic mechanisms.

Chronic AT1 receptor blockade alters aortic nerve activity in hypertension.

In the chronic phase of coarctation hypertension (CH) we have shown both reduction in baroreceptor sensitivity (Hypertension. 1992;19[suppl II]:II-198-II-201.) and normalization of the depressed baroreceptor reflex control of heart rate, even with the persistence of hypertension in losartan-treated animals (Am J Physiol. 1995;269:H812-H818). In the present study we analyzed the effects of angiotensin II blockade on afferent aortic nerve activity of CH and sham-operated groups treated chronically with vehicle or losartan (10 mg/kg per day p.o.). CH was induced by subdiaphragmatic aortic coarctation, and the treatments lasted 8 days (4 control and 4 experimental days). Aortic pressure (conscious rats) and aortic nerve activity simultaneous to pressure (anesthetized rats) were recorded on the fourth day of the experimental period. Losartan-treated rats showed reduced tail pressure (104+/-3 versus 117+/-3 mm Hg in the vehicle group). In both groups, aortic coarctation caused a significant increase in pressure (25% and 28%, respectively) and a depression of the aortic nerve activity/pressure relationship when compared with sham-operated coarcted animals. In the physiological range of pressure changes, the depression was significantly smaller after losartan treatment (3.30+/-0.33 versus 2.18+/-0.37%/mm Hg in the losartan- and vehicle-treated CH groups, respectively, versus 5.05+/-0.33%/mm Hg in the sham-operated vehicle-treated group). Angiotensin type 1 (AT1) receptor blockade was also accompanied by reduced variability of the afferent discharge. The data suggested that apart from its pressure effect, angiotensin II acts at AT1 receptors to decrease the sensitivity of aortic afferents during physiological (+/-10 mm Hg) increases and decreases in pressure. Thus, angiotensin II may contribute to reductions of baroreceptor gain in chronic hypertension.

Activation of P2X receptors for adenosine triphosphate evokes cardiorespiratory reflexes in anaesthetized rats.

1. We tested the hypothesis that activation of P2X receptors associated with vagal afferent nerves can evoke a Bezold-Jarisch (B-J) depressor reflex in anaesthetized rats. 2. Injection of alphabeta-methylene ATP (alphabeta-MeATP; 0.6-600 nmol i.v.) evoked a dose-dependent B-J reflex comprising bradycardia, hypotension and apnoea in rats anaesthetized with pentobarbitone. Apnoea was commonly preceded by hyperventilation. Bilateral vagotomy significantly reduced the bradycardia and most of the apnoeic response without affecting hyperventilation, and unmasked a vasopressor response. Hypotension and apnoea were subject to desensitization, and ATP was about 100 times less potent than alphabeta-MeATP in evoking the B-J reflex. 3. ED50 values for responses to alphabeta-MeATP were: bradycardia 14.6 +/- 3.8 nmol; apnoea 47.1 +/- 8.5 nmol; hyperventilation 23.3 +/- 6.0 nmol, n = 14. The ED50 for apnoea was significantly greater than that for bradycardia or hyperventilation (P < 0.05). Atropine (2.8 micromol (kg body wt)-1 i.v.) antagonized the reflex bradycardia and hypotension. 4. The P2 antagonists suramin (14 micromol (kg body wt)-1 i.v.) and PPADS (17 micromol (kg body wt)-1 i.v.) antagonized the bradycardic and apnoeic components of the reflex response to alphabeta-MeATP, without reducing the vasopressor or hyperventilatory responses to the agonist. 5. Recordings from vagal afferents showed that pulmonary inflation receptors were activated by alphabeta-MeATP in 62 % of units recorded (ED50 22 +/- 5 nmol) and this was blocked by PPADS (17 micromol (kg body wt)-1 i.v.); unidentified vagal afferents were also activated. 6. alphabeta-MeATP activated carotid chemoreceptor afferents (ED50 23 +/- 9 nmol), an action that was unaffected by PPADS or suramin. 7. The results support the hypothesis that P2X receptor subtypes for ATP are associated with specific sensory nerves that form part of the homeostatic mechanism for cardiovascular and respiratory regulation and these receptors therefore have physiological, pathological and therapeutic significance.

The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates.

The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation. The identification of the SCA2 mutation in 31 out of 38 families with the ADCA I phenotype, but in none of those with ADCA II, ADCA III or ILOCA confirms the specificity of this mutation. A clinical comparison of the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences between the groups; SCA2 patients tended to have a longer disease duration, a higher frequency of slow saccades and depressed tendon reflexes. However, these neurological signs were also seen in an ADCA I family in which the SCA2 mutation was not identified, illustrating the importance of a direct genetic test. The SCA2 families were from different geographical and ethnic backgrounds. However, haplotype analysis failed to show evidence of a founder mutation, even in families from the same geographical origin. The range of normal alleles varied from 17 to 30 CAG repeats and from 35 to 51 repeats for the pathological alleles. Similar to the other diseases caused by unstable trinucleotide repeats, a significant inverse correlation has been found between the number of repeats and age of onset, and there is a significantly higher paternal instability of repeat length on transmission to offspring. The SCA2 mutation is the most frequent amongst ADCA I patients, accounting for 40%, compared with SCA1 and SCA3 which account for 35% and 15%, respectively.

Phasic and tonic reflexes evoked in human antagonistic wrist muscles by tendon vibration

The electromyographic reflex responses of the voluntarily contracting wrist flexor and extensor muscles to periods of vibration-evoked enhanced, Ia-dominated afferent discharge from flexor carpi radialis (FCR) were studied in normal human subjects. Three main response phases were characterised, namely, (i) phasic `on' responses elicited at the commencement of stimulation, (ii) tonic response levels occurring during prolonged stimulation and (iii) phasic `off' responses elicited at the termination of stimulation. The phasic `on' reflex responses of FCR and extensor carpi radialis (ECR) comprised, respectively, a peak of autogenetic excitation of group mean latency 18.8 ms and a trough of reciprocal inhibition of group mean latency 38.0 ms. Prolonged (2 s) trains of FCR (agonist) vibration evoked a phase of tonic reflex excitation in FCR whose mean level was significantly increased, by 20%, above pre-stimulus activity and which did not change over the 0.5–2.0 s vibration period. Progressive reduction of the duration (from 2000 ms to 100 ms) of vibration trains demonstrated that phasic disfacilitatory `off' troughs regularly occurred, with a consistent latency (mean 24.2 ms), on withdrawal of each period of enhanced Ia-input. This indicates that the responsible excitatory reflex mechanism was operational for the entire duration of each of the vibration periods tested. The extra latency (on average 5.4 ms) of phasic `off' relative to `on' responses may be attributed to factors (e.g. 5–10 ms duration of unitary muscle action potentials and afterdischarge in reflex pathways) which inevitably delay the appearance of overt disfacilitatory reductions in EMG rather than the involvement of different reflex pathways. Thus, short-latency, possibly monosynaptic, reflex excitation contributed throughout the entire tonic excitatory response. Sustained FCR (antagonist) vibration produced a significant tonic reciprocal inhibitory reflex depression, by 7% pre-stimulus EMG, of ECR activity which remained steady during the 0.5–2.0 s vibration period. The absence of well-defined phasic disinhibitory `off' responses in ECR suggests that the contribution of oligosynaptic reflex inhibitory mechanisms to the tonic suppression of activity occurring during continuing vibration is relatively small.

Peripheral neuropathy in HIV disease.

Neurologic disorders are among the most common and devastating complications of HIV infection and AIDS.1 As patients with HIV infection survive longer in the era of HAART, it is likely that the prevalence of these disorders will increase. Peripheral nerve disorders are the most common neurologic complication of HIV disease.2 HIV-related peripheral nerve disorders include distal symmetric polyneuropathy (DSP), acute or chronic inflammatory demyelinating polyneuropathy (IDP), mononeuritis multiplex (MM), progressive polyradiculopathy (PP), and autonomic neuropathy (AN). Data from ACTG protocol 175 indicate that neuropathy is frequently misdiagnosed, even by experienced clinicians.3 In order to provide effective treatment, it is essential to distinguish among the various forms of neuropathy and to correctly attribute them to primary HIV infection or to other causes, such as the neurotoxic effects of antiviral agents. Although peripheral neuropathy is generally not a life-threatening disease, the debilitating pain can severely impair the quality of life of affected individuals. Of particular importance is distal sensory polyneuropathy (DSP), the most common form of peripheral neuropathy and the only one associated with the use of antiretroviral therapy. DSP affects over one third of patients with AIDS. It is rarely seen in children and is most common in the late stages of HIV disease. The clinical symptoms of DSP are numbness, burning, and tingling sensations in the feet, usually in a symmetric pattern; paresthesias or aching distally in the lower extremities; and hyperesthesia (e.g., contact sensitivity, such as with bedsheets or socks). Individuals with DSP may alter their gait in order to avoid painful pressure on their feet, which can result from even light contact. In late stages of DSP, the upper extremities may also be affected, although to a milder degree. Neurologic examination reveals depressed or absent ankle reflexes relative to the knees. While this is a …

Contribution of C-fiber afferent nerves and autonomic pathways in the urinary bladder to spinal c-fos expression induced by bladder irritation

Previous studies have revealed that chemical irritation of the urinary bladder and urethral mucosa increases the expression of the immediate-early gene, c-fos, in the lumbosacral spinal cord of the rat. The present experiments were undertaken to determine whether drugs known to suppress bladder reflex pathways or spinal nociceptive mechanisms would influence c-fos expression induced by chemical irritation of the lower urinary tract (LUT). Capsaicin (100 mg/kg subcutaneous (sc), 7 days prior to the experiment) which does not block bladder reflexes but does desensitize C-fiber afferents, reduced (89%) the number of Fos-positive cells in the lumbosacral spinal cord induced by acetic acid-induced irritation of the LUT. Morphine (2.5 mg/kg, intravenous (iv)) or a low dose of baclofen, a GABAB agonist, both of which markedly suppressed reflex bladder activity, did not alter spinal c-fos expression induced by LUT irritation. However, a larger dose of baclofen (10 mg/kg, iv) reduced by 45% the number of Fos-positive cells. Clonidine (200 mug/kg, iv), an alpha2 adrenergic agonist, depressed bladder reflexes but produced only a small decrease (25%) in c-fos expression in lateral laminae V-VII of the cord. The ganglionic blocking agent, hexamethonium, which blocks autonomic but not afferent pathways to the LUT, decreased c-fos expression by 50%. The results indicate that certain drugs can differentially affect reflex bladder activity and c-fos expression and that analgesic drugs which suppress somatic nociceptive pathways do not necessarily affect the c-fos expression induced by visceral nociceptive input.

Brainstem microstimulation differentially inhibits pudendal motoneuron reflex inputs.

Sensory information from the genitourinary tract is transmitted to perineal muscle reflex circuits in the spinal cord and to the medullary reticular formation (MRF). This is the first report of a functional descending connection between neurons in the MRF and sensory inputs of the pudendal motoneuron reflex circuitry. In anesthetized rats, microstimulation of the MRF produced a decrease in amplitude and increase in latency of pudendal motoneuron reflex discharges (PMRD) elicited by stimulation of the dorsal nerve of the penis. No effects on pelvic nerve-elicited PMRD were found. The most robust reflex depression was observed when the lateral paragigantocellular reticular nucleus was microstimulated bilaterally. Reproductive abnormalities that occur following severe spinal cord injury probably result from disruption of these descending connections.

Automated Pupil Perimetry in Amblyopia: Generalized Depression in the Involved Eye

This study was designed to determine whether the relative afferent pupillary defects observed commonly in amblyopic eyes are associated with a uniform depression of the pupillary light reflex throughout the visual field or solely by a focal decrease in pupillary response near fixation. The authors used pupil perimetry to evaluate the contraction amplitude of the pupil in response to focal light stimuli at 76 points throughout the 30 degrees field in each eye of 28 patients with amblyopia. The "pupil fields" were recorded using a computerized infrared pupillograph linked to a Humphrey Field Analyzer, so that the pupil contraction could be recorded in response to perimetric light stimuli. Nine patients had strabismic amblyopia, ten had anisometropia, six had a combination of anisometropia and strabismus, and three had deprivation amblyopia due to monocular congenital cataract. Mean pupillary contraction amplitude for the entire field and focal amplitudes at each tested location were compared. Mixed-model analysis of variance was used to assess effects of perimetry location, type of amblyopia, and interaction effects. The overall average of all the pupil contractions throughout the 30 degrees field was less for the amblyopic eye compared with that of the fellow eye. This decrease in focal pupil response for amblyopic eyes was present in each type of amblyopia and was greatest for deprivation amblyopia. The contraction amplitude was depressed diffusely throughout the pupil field and showed neither focal deficits nor a selective depression about fixation. Amblyopia produces a global depression of focal pupillary responses across the entire 30 degrees field.

Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications.

In chronic heart failure (CHF), arterial baroreflex regulation of cardiac function is impaired, leading to a reduction in the tonic restraining influence on the sympathetic nervous system. Because baroreflex sensitivity (BRS), as assessed by the phenylephrine technique, significantly contributes to postinfarction risk stratification, the aim of the present study was to evaluate whether in CHF patients a depressed BRS is associated with a worse clinical hemodynamic status and unfavorable outcome. BRS was assessed in 282 CHF patients in sinus rhythm receiving stable medical therapy (age, 52+/-9 years; New York Heart Association [NYHA] class, 2.4+/-0.6; left ventricular ejection fraction [LVEF], 23+/-6%). The BRS of the entire population averaged 3.9+/-4.0 ms/mm Hg (mean+/-SD) and was significantly related to LVEF and hemodynamic parameters (LVEF, P<.005; cardiac index and pulmonary wedge pressure, P<.001 by regression analysis). Patients in NYHA classes III or IV and those with severe mitral regurgitation had markedly depressed vagal reflexes. The association of BRS with survival was described after its categorization in three groups: below the lowest quartile (<1.3 ms/mm Hg), between the lowest quartile and the median (1.3 to 3 ms/mm Hg), and above the median (>3 ms/mm Hg). During a mean follow-up of 15+/-12 months, 78 primary events (cardiac death, nonfatal cardiac arrest, and status 1 priority transplantation) occurred (27.6%). BRS was significantly related to outcome (log rank, 9.1; P<.01), with a relative risk of 2.7 (95% confidence interval, 1.6 to 4.7) for patients with the major derangement in BRS (<1.3 ms/mm Hg). At multivariate analysis, BRS was an independent predictor of death after adjustment for noninvasive known risk factors but not when hemodynamic indexes were also considered. In CHF patients with severe mitral regurgitation, however, BRS remained a strong prognostic marker independent of hemodynamic function. In moderate to severe CHF, a depressed sensitivity of vagal reflexes parallels the deterioration of clinical and hemodynamic status and is significantly associated with poor survival. Particularly in patients with severe mitral regurgitation the baroreceptor modulation of heart rate provides prognostic information of incremental value to hemodynamic parameters.

A simple method, using 2-hydroxypropyl- β-cyclodextrin, of administering α-chloralose at room temperature

Effective long term stable anaesthesia is a goal of many drug regimens employed in neuroscience in which procedures carried out are not practical in awake animals. A particular problem is the study of nociceptive mechanisms where good anaesthesia is essential. Similarly studies of cardiovascular or cerebrovascular mechanisms require that normal physiological reflexes be preserved as much as is practical. For non-recovery anaesthesia α-chloralose is a good choice since it provides good anaesthesia without excess depression of physiological reflexes. However, α-chloralose is sparingly soluble so that its use is not straightforward. We describe the characterisation of a simple procedure to solubilise α-chloralose in a solution of 2-hydroxypropyl- β-cyclodextrin. The resulting solution is stable at room temperature and gives a high concentration of α-chloralose making it easier to administer regularly during longer time course experiments.

Selective Depression of the Spinal Polysynaptic Reflex by the NMDA Receptor Antagonists in an Isolated Spinal Cord in vitro

1. The effects of N-methyl-D-aspartate (NMDA) receptor glycine-binding site antagonists 7-chlorokynurenate (7-Clkyn) and (±)-3-amino-1-hydroxy-2-pyrrolidone (HA-966) on spinal reflexes in an isolated spinal cord that was maintained in Mg 2+-free medium in vitro were examined. The actions of 7-Clkyn and HA-966 were compared with those of the channel-site antagonist (i.e., dizocilpine) and NMDA-binding site antagonists—that is, 3-[(±)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) and DL-2-amino-5-phosphonovalerate (APV). 2. 7-Clkyn and HA-966 produced a selective depression of the polysynaptic reflex (PSR) while negligibly affecting the activity of the monosynaptic reflex (MSR). The PSR was also differentially suppressed by dizocilpine, CPP and APV. The PSR inhibitory activity of the NMDA antagonists was in the following order: dizocilpine>CPP>APV=7-Clkyn>HA-966. 3. The inhibitory effects of 7-Clkyn on PSR were markedly antagonized by the simultaneous application of D-serine, an agonist for the NMDA receptor glycine-binding sites. However, PSR inhibition by dizocilpine and CPP was unaffected. 4. Inhibition of the PSR by 7-Clkyn persisted in the presence of strychnine, which markedly increased the PSR activity by itself. 5. These findings suggest that the NMDA receptor glycine-binding sites play a role in generating the NMDA receptor-mediated PSR in the spinal cord in vitro.

Enhancement and depression of spinal reflexes by 8-hydroxy-2-(di-n-propylamino)tetralin in the decerebrated and spinalized rabbit: involvement of 5-HT1A- and non-5-HT1A-receptors.

1. In decerebrated, spinalized and paralyzed rabbits, intravenous administration of the 5-HT1A-receptor agonists (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 3-300 nmol kg(-1), cumulative) and flesinoxan (22-2200 nmol kg(-1), cumulative) significantly increased the short latency reflex evoked in gastrocnemius medialis motoneurones by electrical stimulation of all myelinated afferents (Abeta and Adelta fibres) of the sural nerve. Reflexes increased to median values of 198% (inter-quartile range (IQR) 148-473%) and 296% (IQR 254-522%) of pre-drug values with the highest doses of 8-OH-DPAT and flesinoxan, respectively. The enhancement of reflexes induced by 5-HT1A-receptor agonists was not reversed by the selective 5-HT1A-receptor antagonist (S)WAY-100135 (2.05 micromol kg[-1]). 2. The effects of 8-OH-DPAT were tested after pretreatment with (S)WAY-100135 (2.05 micromol kg[-1]), its more potent analogue WAY-100635 (185 nmol kg[-1]), and the 5-HT2/5-HT1D-/5-HT7-receptor ligand ritanserin (1.67 micromol kg[-1]). 8-OH-DPAT (300 nmol kg(-1) single dose) significantly increased gastrocnemius reflex responses in the presence of (S)WAY-100135 and WAY-100635, to median values of 260% (IQR 171-295%) and 165% (IQR 136-170%) of pre-drug levels, respectively. These values were not significantly different from each other, or from the effects of 8-OH-DPAT given alone. When 8-OH-DPAT was given after ritanserin, reflexes were a median of 102% (IQR 76-148%) of pre-drug values: i.e. there was no significant increase in responses. Neither WAY-100635 nor ritanserin had any effects on reflexes per se. 3. WAY-100635 (185 nmol kg[-1]) and ritanserin (1.67 micromol kg[-1]) were given after 8-OH-DPAT (300 nmol kg[-1]). The agonist increased reflexes to a median value of 184% (IQR 135-289%), after which WAY-100635 significantly reduced responses to 165% (IQR 130-254%) and ritanserin further decreased reflexes to a median of 107% (IQR 100-154%) of pre-drug levels, i.e. not significantly different from controls. 4. Previous studies have shown that reflexes evoked by large myelinated axons tend to be suppressed, rather than enhanced, by 5-HT1A-receptor agonists. When tested against reflexes evoked by stimulation of the sural nerve at strengths between 1.5 and 2.5 times threshold, 8-OH-DPAT (3-300 nmol kg(-1), cumulative) and flesinoxan (22-2200 nmol kg(-1), cumulative) significantly reduced gastrocnemius responses to median values of 36% (IQR 15-75%) and 17% (IQR 12-38%) of pre-drug levels, respectively. This inhibition was fully reversed by (S)WAY-100135 (2.05 micromol kg[-1]). 5. These data show that drugs that are agonists at 5-HT1A-receptors increase polysynaptic spinal reflexes evoked by moderate to high stimulus intensities and depress responses to very low intensity stimuli. The inhibitory effects of these drugs were mediated through 5-HT1A-receptors as they were abolished by a selective antagonist for these sites. However, the facilitatory effects of 8-OH-DPAT could be completely blocked only by a combination of ritanserin, which has no significant affinity for 5-HT1A-receptors, with WAY-100635. It appears that the enhancement of reflexes by 8-OH-DPAT arises from a combined action at 5-HT1A-receptors and other, ritanserin-sensitive, sites which could be 5-HT1D- or 5-HT7-receptors.

Effects of a new centrally acting muscle relaxant, NK433 (lanperisone hydrochloride) on spinal reflexes

(−)-( R)-2-methyl-3-(1-pyrrolidinyl)-4′-trifluoromethylpropiophenone monohydrochloride, lanperisone hydrochloride (NK433) administered intravenously or orally depressed the mono- and polysynaptic reflex potential, dorsal root reflex potential, flexor reflex mediated by group II afferent fibers, patellar and flexor reflexes. These effects were reduced by spinal transection. NK433 inhibited the facilitation of the flexor reflex mediated by group II afferent fibers that was induced by intrathecal administration of noradrenaline–HCl. (+)-(1 R,2 R)-2-methyl-3-(1-pyrrolidinyl)-1-(4-trifluoromethylphenyl)-1-propanol (LPS-9)–HCl, a metabolite of NK433, also inhibited the spinal reflexes. Given orally, NK433 had effects more than three times stronger and tending to be longer-lasting than those of eperisone–HCl. These results suggest that NK433 exerts a non-selective inhibition on spinal reflexes and that inhibition of the descending noradrenergic tonic facilitation within the spinal cord is involved in the mechanism of spinal reflex depression by NK433. LPS-9 could contribute to the potent activity of NK433 after oral administration.

Effects of clomipramine and desipramine on a C-fiber reflex in rats

A C-fiber nociceptive reflex evoked by electrical stimulation within the territory of the sural nerve, was recorded from the ipsilateral biceps femoris muscle in urethane anesthetized rats. Intravenously administered clomipramine and desipramine produced a dose-dependent depression of the C-fiber reflex. High doses of intrathecal desipramine also inhibited the C-fiber reflex, while similar intrathecal doses of clomipramine produced only a modest inhibition of the response. Intracerebroventricular administration of clomipramine decreased dose-dependently the C-fiber reflex whereas intracerebroventricular desipramine increased this reflex. These findings suggest that tricyclic antidepressants with noradrenergic selectivity, as desipramine, inhibit the spinal processing of C inputs by acting directly at the spinal cord level, while those with serotonergic spectra, as clomipramine, depress the C-fiber-evoked spinal reflex by acting at a supraspinal modulatory site.

Testing for pre-synaptic and post-synaptic changes in the soleus H reflex pathway following selective muscle vibration in humans

Muscle vibration does not affect post-synaptic excitability of the corresponding motoneuronal pool, the concurrent depression of the monosynaptic reflex resulting from a pre-motoneuronal block of Ia spindle afferents. Indeed (1) both homonymous and heteronymous soleus responses (to electrical stimulation of the posterior tibial nerve (TN) and femoral nerve (FN), respectively) are clearly depressed during selective vibration of the homologous muscle (namely soleus (S) or quadriceps (Q)), but remain completely unchanged during vibration of the heterologous muscle (i.e. Q or S); (2) the effectiveness of facilitatory conditioning of FN and TN Ia afferents, respectively on the S motoneuronal pool is definitely reduced during vibration of the homologous muscle (namely Q and S).

Chemical stimulation of cardiac receptors attenuates locomotion in mesencephalic cats.

The purpose of the present investigation was to determine whether chemical stimulation of cardiac receptors is sufficient to inhibit locomotion. Decerebrate, unanesthetized cats were induced to walk on a treadmill by electrically stimulating the mesencephalic locomotor region (MLR). Cardiac receptors were stimulated by injecting nicotine (62.3 +/- 8.6 microg/kg, mean +/- SE) into the pericardial sac. Cardiac nerve activity was reversibly blocked by injecting procaine (2%) into the pericardial sac. Locomotion was monitored by using bipolar needle electrodes inserted into the lateral gastrocnemius (LG) and tibialis anterior (TA) muscles. Integrated electromyographic (iEMG) activity from each muscle was quantified on a step-by-step basis. Intrapericardial (ipc) nicotine inhibited locomotion and evoked the coronary chemoreflex. Blood pressure and heart rate decreased significantly by 45.6 +/- 7.1 mmHg and 59.3 +/- 12.3 beats/min, respectively. Nicotine ipc significantly reduced iEMG activity by 24-28% in the LG muscles. The TA muscles were not affected consistently by ipc nicotine. The locomotor inhibition and the depressor reflex paralleled each other and occurred within 5 s of nicotine injection. Procaine ipc blocked the nicotine-induced locomotor inhibition and depressor reflex. The effects of procaine were largely reversible, because ipc nicotine reduced iEMG activity in the LG (25-46%) but not in the TA muscles after washing procaine from the pericardial sac. These results demonstrate that cardiac receptors sensitive to nicotine inhibit MLR-induced locomotion in the decerebrate cat. These findings indicate the presence of a neural pathway from the heart whereby endogenous stimuli could reflexly alter motor control.

Low-frequency depression of the monosynaptic reflex is not altered by tetrodotoxin-induced nerve conduction blockade.

The present study is part of ongoing investigations into activity-related synaptic plasticity in the intact animal. In this investigation we sought to determine whether the previously reported increase in synaptic efficacy at the Ia-motoneuron connection following nerve conduction blockade could be attributed to changes in circuitry external to the monosynaptic pathway. Specifically, we used the phenomena of low-frequency depression of the extracellularly recorded group I monosynaptic reflex (MSR) as an indirect measure of presynaptic inhibition. Tibial nerve conduction blockade was achieved by superfusion of the sodium channel blocker tetrodotoxin (TTX). An osmotic pump delivered the TTX to the tibial branch of the sciatic nerve for a period of either 3 or 10 days. Control rats were either unoperated or received implants of pumps not containing TTX. Data collection consisted of tibial nerve stimulation (0.1-20 Hz) with bilateral recordings of the MSR from the L5 ventral roots. The extent of low-frequency depression was compared between treated and untreated sides of TTX-treated animals and between treated and untreated animals. Results showed that the extent of low-frequency depression was unchanged by either 3 or 10 days of complete blockade of tibial afferents. On the basis of this finding, it is concluded that the previously reported TTX-induced increase in Ia excitatory postsynaptic potential amplitude is unlikely to be due to changes in presynaptic inhibitory pathways.

CI 988, an antagonist of the cholecystokinin-B receptor, potentiates endogenous opioid-mediated antinociception at spinal level

The effects of RB 101 {N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxo-propyl]-L-phenylalanine benzyl ester}, a complete inhibitor of enkephalin-degrading enzymes and CI 988, a selective antagonist of the cholecystokinin (CCK)-B receptors, on the flexor reflex in decerebrate, spinalized, unanaesthetized rats were assessed. Intravenous RB 101 induced a dose-dependent depression of the flexor reflex with a threshold dose of 20 mg/kg and an ED 50 of 25.3 mg/kg. Subcutaneous CI 988 at 1 mg/kg, which by itself did not influence the flexor reflex, strongly enhanced the reflex depressive effect of RB 101. The dose-response curve for RB 101 was shifted to the left and the duration of reflex depression was significantly prolonged. The results confirmed and extended previous behavioural data indicating that blockade of CCK-B receptors potentiated antinociception elicited by endogenous opioids protected from enzymatic degradation. Furthermore, the spinal cord is an important site of interaction between the endogenous opioid and CCK systems.

Ethanol as a general anesthetic: Actions in spinal cord

Ethanol, usually studied in relation to intoxication, is also capable of producing general anesthesia. The most common standard of anesthetic potency is the concentration which produces immobility in response to a noxious stimulus. This concentration will be referred to as the anesthetic concentration. Immobilization is a spinal effect. Ethanol effects were studied in spinal cord from 2–7-day-old rats at concentrations which included the anesthetic concentration in both adult rats (97 mM) and 6–7-day-old rats (235 mM). At neonatal but not adult anesthetic concentrations, ethanol depressed monosynaptic reflex amplitude (mediated by glutamate AMPA receptors + compound action potential). At both neonatal and adult anesthetic concentrations ethanol reversibly depressed the population excitatory postsynaptic potential (pEPSP) (glutamate AMPA and NMDA receptors), the slow ventral root potential (NMDA + metabotropic receptors), and the dorsal root potential (GABA A receptors, via glutamate-excited interneurons). Effects were greater on NMDA receptor-mediated components than on AMPA-receptor-mediated components of the pEPSP and greater on NMDA than on metabotropic receptor-mediated components of the slow ventral root potential. The profile of ethanol effects on spinal cord resembles that of inhalation general anesthetics. The results show that both AMPA and NMDA receptor-mediated transmission are sensitive to ethanol and that enhancement of GABAergic neurotransmission is overridden by depression of excitation to the interneurons. They provide no obvious explanation for ethanol's lower general anesthetic potency in the neonate.