Facilitation Of Reflex Research Articles

Anatomically remote muscle contraction facilitates patellar tendon reflex reinforcement while mental activity does not: a within-participants experimental trial

BackgroundThe Jendrassik maneuver (JM) is a remote facilitation muscular contraction shown to affect amplitude and temporal components of the human stretch reflex. Conflicting theoretical models exist regarding the neurological mechanism related to its ability to reinforce reflex parameters. One mechanism involves the gamma motoneurons of the fusimotor system, which are subject to both physical and mental activity. A second mechanism describes reduced alpha motoneuron presynaptic inhibition, which is not subject to mental activity. In the current study, we determined if mental activity could be used to create a reflex facilitation comparable to a remote muscle contraction.MethodUsing a within-participants design, we investigated the relative effect of the JM and a successfully employed mental task (Stroop task) on the amplitude and temporal components of the patellar tendon reflex.ResultsWe found that the addition of mental activity had no influence on the patellar tendon reflex parameters measured, while the JM provided facilitation (increased reflex amplitude, decreased total reflex time).ConclusionThe findings from this study support the view that the mechanism for the JM is a reduction in presynaptic inhibition of alpha motoneurons as it is influenced by physical and not mental activity.

Facilitation and habituation of the startle reflex over the tonically active biceps brachii muscle contralateral to electrical stimuli

The aim of the present investigation was to explore the impact of muscle contraction on startle reflex responses after electrical stimuli (single or trains of 3) and to study startle reflex habituation. The electromyogram was recorded over the tonically active biceps brachii muscle in 19 healthy subjects contralateral to electrical stimuli (9–12mA) that were delivered at 1.0 and 0.4Hz over the superficial radial nerve. The muscle contraction level was varied by loading weight on the subject's bent arm (0.0, 1.0 or 1.5kg). Furthermore, short term reflex habituation was investigated using 30 blocks of 5 subsequent stimuli. Startle response amplitudes gained significantly (p<0.05) after (i) train stimuli as compared with single stimuli, during (ii) high versus low levels of muscle contraction, and at (iii) 0.4Hz versus 1.0Hz stimuli. Startle reflex amplitudes decreased significantly by the influence of preceding stimuli (p<0.05). This study provides evidence that the startle reflex can be significantly influenced by weight load, i.e. by volitional influences. Startle reflex investigation over a contracted limb muscle results in a high probability of startle release and thereby improved detection of SR habituation following preceding stimuli.

P2X7 receptor blockade reverses purinergic facilitation of neck muscle nociception in mice

Facilitation of neck muscle nociception mediated via purinergic signalling may play a role in the pathophysiology of tension-type headache (TTH). The present study addressed reversal of purinergic facilitation of brainstem nociception via P2X7 antagonist action in anaesthetized mice. Following administration of α,β-meATP (i.m. 20 µL/min, 20 µL each) into semispinal neck muscles, the impact of neck muscle nociceptive input on brainstem processing was monitored by the jaw-opening reflex in anaesthetized mice (n = 20). The hypothesized involvement of the P2X7 receptor in the α,β-meATP effect was addressed with i.p. (systemic) and i.m. (semispinalis, 20 µL/min, 20 µL each) administration of P2X7 inhibitor A438079 during established facilitation; i.p. saline served as control. α,β-meATP reliably induced jaw-opening reflex facilitation (256 ± 48% (mean ± SEM), n = 20). I.p. A438079 (150, 300 µmol/kg) completely reversed this α,β-meATP effect dose-dependently. Neither saline nor intramuscular A438079 (100 µM) altered facilitated brainstem nociceptive processing. These data suggest that muscular structures are not directly involved in the P2X7 antagonist-mediated reversal of purinergic facilitation. Instead, involvement of neuronal structures, particularly of the central nervous system, seems more probable. The results from this animal experimental model may point to involvement of purinergic P2X7 receptors in TTH pathophysiology and may suggest potential future targets for its pharmacological treatment.

A critical period in the supraspinal control of pain: opioid-dependent changes in brainstem rostroventral medulla function in preadolescence

We have previously shown that the balance of electrically evoked descending brainstem control of spinal nociceptive reflexes undergoes a switch from excitation to inhibition in preadolescent rats. Here we show that the same developmental switch occurs when μ-opioid receptor agonists are microinjected into the rostroventral medulla (RVM). Microinjections of the μ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the RVM of lightly anaesthetised adult rats produced a dose-dependent decrease in mechanical nociceptive hindlimb reflex electromyographic activity. However, in preadolescent (postnatal day 21 [P21]) rats, the same doses of DAMGO produced reflex facilitation. RVM microinjection of δ-opioid receptor or GABAA receptor agonists, on the other hand, caused reflex depression at both ages. The μ-opioid receptor-mediated descending facilitation is tonically active in naive preadolescent rats, as microinjection of the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) into the RVM at this age decreases spinal nociceptive reflexes while having no effect in adults. To test whether tonic opioid central activity is required for the preadolescent switch in RVM descending control, naloxone hydrochloride was delivered continuously from subcutaneous osmotic mini-pumps for 7-day periods, at various postnatal stages. Blockade of tonic opioidergic activity from P21 to P28, but not at earlier or later ages, prevented the normal development of descending RVM inhibitory control of spinal nociceptive reflexes. Enhancing opioidergic activity with chronic morphine over P7 to P14 accelerated this development. These results show that descending facilitation of spinal nociception in young animals is mediated by μ-opioid receptor pathways in the RVM. Furthermore, the developmental transition from RVM descending facilitation to inhibition of pain is determined by activity in central opioid networks at a critical period of periadolescence.

Chemical lesioning and glutamate administration reveal a major role for the nucleus tractus solitarius in the cardiac-somatic reflex in rats

Many patients suffer from secondary muscle hyperalgesia after experiencing angina pectoris. In this study, we examined the role of the nucleus tractus solitarius (NTS) and glutamate receptors in modulating cardiac-evoked muscle hyperalgesia induced by pericardial capsaicin, which was monitored by recording electromyogram (EMG) activity from the spinotrapezius muscle in the anesthetized rat. Unilateral chemical lesioning of the commissural NTS with the neurotoxin ibotenic acid significantly depressed the cardiac-somatic reflex; the EMG responses decreased to 56.4±6.9% of that of the controls (5 of 5). Microinjection of the excitatory amino acid glutamate, at 10, 20, and 50 nmol, into the commissural NTS increased the EMG response, in a dose-dependent manner, to 116.9±4.9%, 143.9±10.2%, and 214.2±15.8% (n=8), respectively, of that of the controls. In contrast, microinjection of the N-methyl-d-aspartate (NMDA) receptor antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo [a, d]-cyclohepten-5,10-imine maleate (MK-801) at 4 and 6 nmol, decreased the EMG response to 45.2±10.6% and 36.8±14.3%, respectively, of that of the controls (n=8 for each dose). Similarly, the metabotropic glutamate receptor (mGluR) antagonist (RS)-a-methyl-4-carboxyphenylglycine (MCPG), at 2.5 and 5 nmol, decreased the EMG response to 65.2±16.3% and 57.0±4.2%, respectively, of that of the controls. When a combination of MK-801 and MCPG was administrated, the EMG response further decreased to 22.5±13.2% (n=6) of that of the controls. However, administration of a non-NMDA receptor antagonist 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), at 2 and 5 nmol, had no effect on the EMG response. These results suggest that the NTS is involved in the facilitation of the cardiac-somatic reflex, and that the NMDA receptor and mGluRs play an important role in mediating this effect.

Origin of the low-level EMG during the silent period following transcranial magnetic stimulation

ObjectiveThe cortical silent period refers to a period of near silence in the electromyogram (EMG) after transcranial magnetic stimulation (TMS) of the motor cortex during contraction. However, low-level EMG of unknown origin is often present. We hypothesised that it arises through spinal reflexes. Sudden lengthening of the muscle as force drops during the silent period could excite muscle spindles and facilitate motoneurones. MethodsSubjects (n=8) performed maximal isometric, shortening and lengthening contractions of the elbow flexors during which TMS (90–100% output) was delivered over the motor cortex. The rate of flexion during shortening contractions reduced muscle lengthening caused by muscle relaxation. Surface EMG was recorded from biceps brachii and brachioradialis, and the low-level EMG during silent periods produced by TMS was measured. ResultsLow-level EMG activity was reduced on average by 68% in biceps and 63% in brachioradialis in the shortening contraction compared to all other contraction conditions (p<0.001). Levels of pre-stimulus EMG were similar between conditions. ConclusionsMuscle lengthening contributes to low-level EMG activity in the silent period, through spinal reflex facilitation by muscle spindle afferents. SignificanceThe silent period depth is not only dependent on cortical output but also reflex effects evoked by muscle lengthening.

Botulinum toxin A modulates afferent fibers in neurogenic detrusor overactivity

Although botulinum toxin (BoNT/A) injected into the detrusor muscle improves overactive bladder symptoms in patients with neurogenic detrusor overactivity, how it does so remains unclear. In this study, we investigated whether BoNT/A improves detrusor overactivity by modulating bladder afferent activity. To do so, during urodynamic assessment, we tested the soleus muscle Hoffmann (H) reflex during bladder filling before and after intradetrusor BoNT/A in patients with Parkinson's disease (PD) and in patients with complete chronic spinal cord lesion (SCI) and detrusor overactivity refractory to conventional therapy. Healthy subjects underwent H reflex studies during urodynamic assessment and acted as controls. Our findings show that BoNT/A injected into the detrusor muscle effectively reduces clinical overactive bladder symptoms in patients with PD and SCI. In healthy subjects and patients with PD, bladder filling [at maximum cystometric capacity, (MCC)] significantly decreased the H reflex size, whereas in patients with SCI, it slightly facilitated the H reflex size. At MCC, in patients with PD, BoNT/A significantly reduced the expected H reflex inhibition, whereas in those with SCI, BoNT/A turned the H reflex facilitation at maximum bladder filling into a slight inhibition. These findings show that BoNT/A injected into the detrusor muscle in patients with PD and SCI modulates bladder afferent activity. Modulation of bladder afferents possibly explains why BoNT/A improves detrusor overactivity.

Acetylsalicylic acid inhibits α,β-meATP-induced facilitation of neck muscle nociception in mice — Implications for acute treatment of tension-type headache

Infusion of α,β-methylene ATP (α,β-meATP) into murine neck muscle facilitates brainstem nociception. This animal experimental model is suggested to be appropriate for investigating pathophysiological mechanisms in tension-type headache. It was hypothesized that d-lysine acetylsalicylic acid (ASA, aspirin®) reverses this α,β-meATP effect. Facilitation of neck muscle nociceptive processing was induced via bilateral infusion of α,β-meATP into semispinal neck muscles (100 nM, 20 μl each) in 42 anesthetized mice. Brainstem nociception was monitored by the jaw-opening reflex elicited via electrical tongue stimulation. The hypothesis was addressed by subsequent (15, 30, 60 mg/kg) and preceding (60 mg/kg) intraperitoneal ASA injection. Saline served as control to ASA solution. Subsequent ASA dose-dependently reversed α,β-meATP-induced reflex facilitation and was the most prominent with 60 mg/kg. Preceding 60 mg/kg ASA prevented reflex facilitation. Cyclooxygenases are involved in nociceptive transmission. Former experiments showed that unspecific inhibition of cyclooxygenases does not alter the α,β-meATP effect. This suggests a specific mode of action of ASA. The concept is accepted that neck muscle nociception is involved in the pathophysiology of tension-type headache. Thus, objective proof of ASA effects in this experimental model may emphasize its major role in pharmacological treatment of tension-type headache attacks.

Role of L-DOPA in Spinal Nociceptive Reflex Activity: Higher Sensitivity of Aδ Versus C Fibre-Evoked Nociceptive Reflexes to L-DOPA

The role of L-DOPA in spinal nociceptive reflex activity has been re-evaluated. In high spinal cats, with supraspinal loops being excluded, the onset of reflex facilitation induced by noxious radiant heat is delayed after injection of L-DOPA by 4 to 10 s, i.e. the early component of nociceptive reflex facilitation is blocked, while the late component persisted. Further investigations have shown that the early component of reflex facilitation induced by noxious radiant heat is mediated by Adelta-fibres and the late component by C-fibres. Therefore, it can be assumed that L-DOPA, like opioids, preferentially blocks the transmission in nociceptive reflex pathways from Adelta-fibres.

Facilitation of postural limb reflexes in spinal rabbits by serotonergic agonist administration, epidural electrical stimulation, and postural training

In quadrupeds, spinalization in the thoracic region severely impairs postural control in the hindquarters. The goal of this study was to improve postural functions in chronic spinal rabbits by regular application of different factors: intrathecal injection of the 5-HT(2) agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), epidural electrical spinal cord stimulation (EES), and specific postural training (SPT). The factors were used either alone (SPT group) or in combination (DOI+SPT, EES+SPT, and DOI+EES+SPT groups) or not used (control group). It was found that in none of these groups did normal postural corrective movements in response to lateral tilts of the supporting platform reappear within the month of treatment. In control group, reduced irregular electromyographic (EMG) responses, either correctly or incorrectly phased in relation to tilts, were observed. By contrast, in DOI+SPT and EES+SPT groups, a gradual threefold increase in the proportion of correctly phased EMG responses (compared with control) was observed. The increase was smaller in DOI+EES+SPT and SPT groups. Dissimilarly to these long-term effects, short-term effects of DOI and EES were weak or absent. In addition, gradual development of oscillatory EMG activity in the responses to tilts, characteristic for the control group, was retarded in DOI+SPT, EES+SPT, DOI+EES+SPT, and SPT groups. Thus regular application of the three tested factors and their combinations caused progressive, long-lasting plastic changes in the isolated spinal networks, resulting in the facilitation of spinal postural reflexes and in the retardation of the development of oscillatory EMG activity. The facilitated reflexes, however, were insufficient for normal postural functions.

Dose-dependent opposite effects of gabapentin on the depressive action of morphine on a C-fibre reflex in the rat

Gabapentin is a structural analogue of gamma-amino-butyric acid with anticonvulsant activity. Recently, indications for its use were extended to the management of acute pain in the postoperative period. The effects of pre-administration of gabapentin on the depressive action of intravenous morphine were studied on the C-fibre reflex elicited by a wide range of stimulus intensities. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats with either an intact neuraxis or a brainstem previously transected at the level of the obex. As previously reported, 6 mg/kg intravenous morphine both increased the threshold and decreased the slope of the stimulus–response recruitment curve. The C-fibre reflex was not modified following intravenous gabapentin. Gabapentin pre-treatment at lower doses (0.01–7.5 mg/kg) not only antagonized the depressive effect of morphine, but caused facilitation of the reflex. At higher doses (10–50 mg/kg), gabapentin pre-treatment potentiated the depressive effect of morphine. In obex-transected rats, the facilitation of the C-fibre reflex, seen following 1 mg/kg gabapentin and 6 mg/kg morphine, disappeared and was replaced by a strong reinforcement of the depressive effect of morphine. It is concluded that a strong synergy between the effects of gabapentin and morphine can be seen at the spinal level. However, radically opposite effects with supraspinal origins thwart this mechanism. From the clinical standpoint, these results incite cautiousness in the use of combinations of gabapentin and opioids.

Interactions of Apomorphine and a Novel Neuroleptic Dibenzodioxazocine Derivative, as Evidenced by Changes of Somato-autonomic Reflexes and Spontaneous Sympathetic Activity in Cats

The apomorphine-antagonistic effects of EGYT-2509, a novel neuroleptic compound, has been studied by two different methods suitable for investigating the dopaminergic modulation of sympathetic output. (1) In cats lightly anaesthetized with urethane (600 mg kg-1 i.p.), blood pressure (BP) reflexes evoked by electrical stimulation of the sciatic nerve were inhibited by apomorphine (0.2 mg kg-1 i.v.) at low frequencies of stimuli (2-8 Hz), while the BP reflexes were facilitated by apomorphine at higher frequencies of stimulation; the evoked contractions of the nictitating membrane were depressed in the entire range of frequencies applied. EGYT-2509 (1.5 mg kg-1 i.v.) antagonized both the inhibition and facilitation of pressor reflexes induced by apomorphine. EGYT-2509, given alone, in doses exceeding 1.5 mg kg-1 either did not influence or inhibited the responses of nictitating membrane and of BP; the inhibition could be antagonized by haloperidol. The apomorphine-induced sustained hypotension was inhibited by EGYT-2509 (18.5 mg kg-1): after EGYT-2509, higher doses of apomorphine (0.7 vs 0.2 mg kg-1) were required for the effect. Sustained hypotension could be elicited by EGYT-2509, too; after apomorphine, smaller doses of EGYT-2509 (8.5 vs 18.5 mg kg-1) were enough to decrease BP. (2) In cats anaesthetized with chloralose and urethane (50 and 400 mg kg-1 i.p., respectively), apomorphine (0.2 mg kg-1) inhibited the spontaneous activity of the postganglionic renal sympathetic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

In-vivo pharmacological studies of 2-N-carboxamidinonormianserin, a histamine and 5-hydroxytryptamine antagonist lacking central effects.

The in-vivo pharmacological properties have been examined of FCC5 (2-N-carboxamidino-1,2,-3, 4, 10, 14b-hexahydrodibenzo (c.f.) pyrazino (1, 2-alpha)azepine hydrochloride), a guanidino analogue of mianserin. FCC5 (30-100 micrograms kg-1, i.v.) caused long-lasting (> 1 h) attenuation of histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in the anaesthetized guinea-pig. FCC5 (< or = 1 mg kg-1, i.v.) had no effect on submaximal bronchoconstrictor responses caused by i.v. acetylcholine or the thromboxane A2-mimetic U46619 ((15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid). The pressor effects of 5-HT in anaesthetized and pithed rats were inhibited by FCC5 (0.3-1.0 mg kg-1, i.v.). Higher doses of FCC5 (3 mg kg-1, i.v.) reduced bradycardia and depressor responses to 5-HT in anaesthetized rats. In anaesthetized cats and rats and also pithed rats, FCC5 (0.1-1.0 mg kg-1, i.v.) caused sympathomimetic effects as demonstrated by pressor responses and tachycardia. FCC5 (0.1-0.3 mg kg-1, i.v.) inhibited pressor responses to tyramine whereas those to noradrenaline and sympathetic nerve stimulation were potentiated. Oedema in the rat paw caused by intraplantar 5-HT was inhibited by FCC5 (ID50 0.76 mg kg-1, i.p.; and 2.7 mg kg-1, p.o.). In decerebrate rats which had been spinalized at T6-8, fenfluramine-induced facilitation of the flexor reflex of the anterior tibialis muscle was inhibited by mianserin (ID50 0.36 mg kg-1, i.p.) but not by FCC5 (< or = 3 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Neuronal Nitric Oxide Synthase is Involved in the Induction of Nerve Growth Factor‐Induced Neck Muscle Nociception

Neck muscle nociception mediated by nitric oxide may play a role in the pathophysiology of tension-type headache. The present study addresses the involvement of neuronal nitric oxide synthase (nNOS) in the facilitation of neck muscle nociception after local application of nerve growth factor (NGF). After administration of NGF into semispinal neck muscles, the impact of neck muscle noxious input on brainstem processing was monitored by the jaw-opening reflex in anesthetized mice. The modulatory effect of preceding and subsequent administration of an inhibitor of neuronal nitric oxide synthase on central facilitation was addressed in a controlled study. With preceding i.p. application of saline or 0.096 mg/kg of the specific nNOS inhibitor Nω-propyl-L-arginine (NPLA), NGF induced a sustained reflex facilitation within 60 minutes. Preceding injection of 0.96 mg/kg or 1.92 mg/kg NPLA completely prevented the potentially facilitatory effect of NGF. Subsequent administration of 0.96 mg/kg NPLA did not affect established NGF-evoked reflex facilitation. Thus, NPLA prevents facilitation of brainstem processing by noxious myofascial input from neck muscles in a dose-dependent manner. These findings suggest that nNOS is involved in the induction but not the maintenance of NGF-evoked facilitation of nociception in the brainstem. These results from an experimental animal model may support the idea of NOS and nNOS as potential targets for pharmacological treatment of tension-type headache.

Cyclophosphamide induces NR2B phosphorylation-dependent facilitation on spinal reflex potentiation

It is well-established that cyclophosphamide (CYP) can sensitize the pelvic afferent nerve arising from the urinary bladder and therefore induce suprapubic pain. To test the possibility that CYP might mediate the development of visceral hypereflexia/hyperalgesia by facilitating spinal activity-dependent neural plasticity, we compared the pelvic-urethra reflex activity and spinal N-methyl-d-aspartate receptor NR2B subunit (NR2B) phosphorylation in rats treated with vehicle solution and CYP. Compared with vehicle solution, when accompanied by upregulation of phosphorylated NR2B expression in the lumbosacral (L(6)-S(2)) dorsal horn, CYP increased the evoked spikes in spinal reflex potentiation induced by repetitive stimulation (1 stimulation/1 s). Moreover, intraperitoneal pretreatments with N(G)-nitro-l-arginine methyl ester and roscovitine, nitric oxide synthase and cyclin-dependent protein kinase 5 (Cdk5) antagonists, respectively, overwrote CYP-enhanced reflex potentiation and NR2B phosphorylation. When compared with the untreated group, the treatment with small-interfering RNA of NR2B, which decreased the expression of NR2B expression, abolished CYP-dependent reflex facilitation and spinal NR2B phosphorylation. These results suggested that CYP might facilitate spinal reflex potentiation mediated by N-methyl-d-aspartate receptors and participate in the development of visceral hypereflexia/hyperalgesia through nitric oxide- and Cdk5-dependent NR2B phosphorylation at the lumbosacral dorsal horn.

Activation of Neurons of the Medullary Centers of the Autonomic Nervous System Related to Motivated Operant Movements Realized by Rats

Using the corresponding techniques, we visualized Fos-immunoreactive (Fos-ir) and NADPH diaphorasereactive (NADPH-dr) neurons in the medullary centers of the autonomic nervous system (ANS) of rats, which performed repetitive operant movements (catching of food globules from the manger by the left forelimb under conditions of high food motivation). Animals were trained to perform operant movements in 30 min-long everyday sessions during 12 days. The duration of a single food-procuring movement was about 600 msec. Realization of the operant reflex was accompanied by clearly expressed motivational/affective reactions. The heart rate (HR) in the course of each operant movement sharply dropped (on the 10th day of training, by 12%, on average) with subsequent recovery of this parameter within 3–4 sec. In the course of 30-min-long training sessions, the mean HR gradually decreased (in the examined group, 7%, on average) within an interval from the 5th to the 20th min with subsequent recovery until the end of the training session. The mean numbers of Fos-ir neurons in the medullary nuclei of the ANS (Sol, IRt, CVL, RVL, Amb, 10, and MdD) of rats performing food-procuring movements (n = 4) were significantly (P IRt > CVL+RVL/CVL > RVL. Large Fos-ir neurons were observed in the dorsal motor nucleus of the n. vagus (10) and in the Amb/RAmb nuclei. In a considerable proportion of neurons of the Sol and single cells of the 10 and Amb, we observed double labeling (Fos-ir + NADPH-dr). Thus, operant food-procuring movements are accompanied by episodes of bradycardia related to each separate realization; in addition, a long-lasting tonic decrease in the HR developed. These autonomic reactions are mediated by the abovementioned medullary ANS nuclei. It is supposed that the respective weakening of inhibitory sympathetic effects on spindle receptors of the muscles involved in realization of the above operant movements can provide facilitation of generation of proprioceptive impulsation, facilitation of monosynaptic spinal reflexes, and, finally, an increase in the efficacy of targeted limb movements directed toward food procurement.

Spinal motor actions of the μ-opioid receptor agonist DAMGO in the cat

For further evaluation of opioidergic spinal motor functions the action of the μ-opioid receptor agonist DAMGO was tested on transmission in different non-nociceptive and nociceptive spinal reflex pathways from flexor reflex afferents (FRA), and in non-FRA reflex pathways in spinal cats. The action of DAMGO was complex, not following a simple pattern with selective depression of nociceptive pathways compared to non-nociceptive ones. Monosynaptic reflexes of the flexor posterior biceps semitendinosus (PBSt) and transmission in nociceptive as well as non-nociceptive excitatory FRA pathways to PBSt were depressed, while the specific excitatory nociceptive non-FRA pathway from the central foot pad to foot extensors was mainly not depressed but rather facilitated by DAMGO. DAMGO caused a facilitation of monosynaptic reflexes to the extensor gastrocnemius soleus (GS) and partly a reversal of inhibitory to excitatory conditioning effects from cutaneous afferents to GS. FRA interneurones could show either an increase or a cessation of their spontaneous activity, but responsiveness to nociceptive and non-nociceptive afferent activation was blocked by DAMGO. The main DAMGO action is generated via interneuronal systems rather than on motoneurones themselves. The results indicate that opioidergic spinal functions are extensively involved in spinal motor control exceeding a mere suppression of nociceptive motor withdrawal reactions.

Inhibition of nNOS prevents and inhibition of iNOS reverses α,β-meATP-induced facilitation of neck muscle nociception in mice

Infusion of α,β-methylene ATP (α,β-meATP) into murine neck muscle facilitates brainstem nociception. Unspecific nitric oxide synthase (NOS) inhibition prevents and reverses this sensitization. It is unclear whether neuronal (nNOS), inducible (iNOS) or endothelial NOS isoenzymes are involved in this α,β-meATP effect. Hypothesized involvement of nNOS isoenzyme was addressed by preceding (0.5, 1, and 2 mg/kg) and subsequent (2 mg/kg) intraperitoneal injection of the nNOS-inhibitor NPLA. iNOS involvement was addressed by subsequent, intraperitoneal administration of the iNOS-inhibitor 1400 W (2 mg/kg). Brainstem nociception was monitored by the jaw-opening reflex elicited via electrical tongue stimulation in 45 anesthetized mice. Preceding NPLA dose-dependently prevented α,β-meATP-induced reflex facilitation. Whereas subsequent inhibition of nNOS showed no effect, iNOS inhibition by 1400 W significantly reversed reflex facilitation. Data provide evidence that nNOS plays a major role in induction and iNOS in maintenance of facilitation in neck muscle nociception. Divergent roles of NOS isoenzymes may promote research on target specific treatment for headache and neck muscle pain.

Facilitation of a Somatic Reflex by Sound in Rana clamitans: Effects of Sympathectomy and Decerebration1

Summary 1. A tactually elicited leg flexion in Rana clamitans melanota is facilitated by a short sound of a bell preceding application of the effective stimulus by 0.1 to 0.2 sec. The sound alone elicits no overt response. 2. Sympathectomy markedly reduces the intersensory facilitation of the leg flexion reflex. It is suggested that such depression occurs because of reduced central nervous responsiveness following reduction of sympathetically elicited somatic sensory inflow. 3. The frogs readily adapt to the sound of the bell, even when presented with this stimulus every other day. 4. Mid-diencephalic decerebration negates previous adaptation to the sound of the bell, bringing a return of intersensory facilitation of the reflex. 5. These results emphasize the possibility of a vertebrate arousal process which depends upon sympathetic outflow and which may be opposed by a central inhibitory mechanism. Zusammenfassung 1. Das durch einen Schlag ausgeloste Anziehen des Hinterbeins beim gefleckten Schreifrosch (Rana clamitans melanota) verstarkt sich, wenn dem Schlag ein kurzes Klingelzeichen um 0,1 bis 0,2 Sek. vorausgeht (Abb. 1). Die Klingel allein bleibt unbeantwortet. 2. Sympathektomie verringert die intersensorische Bahnung des Beugereflexes des Beines erheblich (Abb. 2), vermutlich auf Grund verringerter zentralnervoser Antwortbereitschaft, die ihrerseits auf einer Verringerung der auf sympathischem Wege ausgelosten somatisch-sensorischen Afferenz beruht. 3. Die Frosche gewohnen sich rasch an die Klingel, deren bahnende Wirkung rasch abnimmt, auch wenn der Reiz nur jeden zweiten Tag geboten wird (Abb. 3, links). 4. Mittelhirnausschaltung hebt die vorherige Gewohnung an die Klingel auf, so das das Horsignal den Beinreflex ebenso bahnt wie zuvor (Abb. 3, rechts). 5. Diese Ergebnisse lassen vermuten, das bei Wirbeltieren ein arousal System besteht, das in seiner Wirkung von sympathischer Efferenz und einem zentralen Hemmungsmechanismus abhangt.

Inhibition of nitric oxide synthases prevents and reverses α,β-meATP-induced neck muscle nociception in mice

Tension-type headache (TTH) is associated with noxious input from neck muscles. Intravenous administration of the unspecific nitric oxide synthase inhibitor L-NMMA in chronic TTH patients caused analgesia and reduction of neck muscle tenderness. The unspecific nitric oxide synthase inhibitor L-NMMA was applied in an experimental model for neck muscle nociception in anesthetized mice (N = 25). Local injection of α,β-meATP into semispinal neck muscles induced sustained facilitation of brainstem nociception as monitored by the jaw-opening reflex. Preceding intraperitoneal administration of L-NMMA (0.05, 0.1, 1 mg/kg) prevented reflex facilitation evoked by α,β-meATP in a dose-dependent manner. Intraperitoneal injection of L-NMMA subsequent to intramuscular α,β-meATP application reversed established brainstem reflex facilitation back to baseline values. Both experiments with preceding and subsequent L-NMMA indicate the involvement of nitric oxide synthases in the induction and maintenance of facilitation. However, future experiments will have to address the involvement of various isoenzymes in order to provide for new therapeutic concepts in TTH.