Experimentally induced spinal nociceptive sensitization increases with migraine frequency: a single-blind controlled study.

The nitric-oxide donor nitroglycerin (NTG) administration induces a facilitation of nociceptive pathways in episodic migraine. This study aims to test the hypothesis that induced spinal sensitization could be more pronounced in patients affected by high-frequency migraine (HF-MIG) with respect to low-frequency migraine (LF-MIG). We enrolled 28 patients with LF-MIG (1-5 migraine days/month), 19 patients with HF-MIG (6-14 migraine days/month), and 21 healthy controls (HCs). Spinal sensitization was evaluated with the neurophysiological recording of the temporal summation threshold (TST) of the nociceptive withdrawal reflex at the lower limb. Temporal summation threshold was recorded at baseline and 30, 60, and 120 minutes after NTG administration (0.9 mg sublingual). Spinal sensitization was detected in LF-MIG at 60 (P = 0.010) and 120 minutes (P = 0.001) and in HF-MIG at 30 (P = 0.008), 60 (P = 0.001), and 120 minutes (P = 0.001) after NTG administration. Temporal summation threshold did not change in HC (P = 0.899). Moreover, TST reduction was more pronounced in HF-MIG with respect to LF-MIG (P = 0.002). The percentage of patients who developed a migraine-like headache after NTG was comparable in the 2 migraine groups (LF-MIG: 53.6%, HF-MIG: 52.6%, P = 0.284), whereas no subjects in the HC group developed a delayed-specific headache. Notably, the latency of headache onset was significantly shorter in the HF-MIG group when compared with the LF-MIG group (P = 0.015). Our data demonstrate a direct relationship between migraine frequency and both neurophysiological and clinical parameters, to suggest an increasing derangement of the nociceptive system control as the disease progresses, probably as a result of the interaction of genetic and environmental factors.

Clinical analgesia correlates with decline in temporal summation in response to remifentanil infusion in patients with chronic neuropathic (radicular) pain.

BACKGROUND: Animal studies have shown that in addition to their antinociceptive effects, opioids have attenuated the electrophysiological "wind-up" phenomenon. Although effects of opioids on clinical pain and on temporal summation (TS), the human correlatives of this phenomenon, have been tested repeatedly, correlations between these two parameters have not been reported so far. OBJECTIVES: To search for possible correlations between the effects of remifentanil on clinical pain intensity and on the magnitude of TS in patients with chronic pain. DESIGN: A single-blinded prospective study. SETTING: A tertiary care pain clinic. PATIENTS: Thirty-one patients (24 men) with chronic lumbar (radicular) neuropathic pain. INTERVENTION: Intervenous administration of saline followed by remifentanil infusions. MAIN OUTCOME MEASURES: Clinical pain intensity and thermal TS measured at baseline, during infusion of each drug and 20 minutes after termination of remifentnail infusion. RESULTS: Friedman test revealed statistically significant differences in the magnitudes of both clinical pain intensity and TS (x(2(3)) = 73, p < 0.001 and x(2(3)) = 11.38, p = 0.01, respectively). Post hoc analysis (Wilcoxon signed-rank test) showed significant differences between clinical pain intensities measured at all time points but significant reductions in the magnitudes of TS were found only during remifentanil compared to baseline (p = 0.014) and to saline (p = 0.019). The difference in clinical pain between saline and remifentanil positively correlated with the difference in TS measured at the same time points (Spearman's test; r = 0.444, p = 0.012). CONCLUSIONS: These results point to a possible causative relationship between TS and opioid analgesia.

Postsynaptic Potentiation in Mouse Motor Synapses Induced by ATP Accumulation in Synaptic Cleft.

In mouse motor synapses, a non-selective purinoceptor antagonist suramin increased the quantum content of endplate potentials (EPP) without changing the time course of synaptic potentials. An ectonucleotidase inhibitor ARL 67156 had no effect on the amplitude and quantum content of EPP and miniature endplate potentials (mEPP) evoked by single stimuli, but significantly prolonged their duration. Long-term high-frequency stimulation of the nerve in the presence of ARL 67156 persistently increased the amplitude and duration of EPP during the train of impulses, but did not change their quantum content. ATP-γ-S, a non-hydrolyzed ATP analogue, significantly increased the amplitudes and prolonged the rising and falling phases of EPP and mEPP. The ATP-induced postsynaptic potentiation in neuromuscular transmission can result from the increase in ATP content and its longer presence in the synaptic cleft.

Temporal summation of pain and ultrasound Doppler activity as predictors of treatment response in patients with rheumatoid arthritis: protocol for the Frederiksberg hospitals Rheumatoid Arthritis, pain assessment and Medical Evaluation (FRAME-cohort) study.

INTRODUCTION: Chronic pain is common in rheumatoid arthritis (RA) and may still persist despite regression of objective signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in RA. Application of the disease activity score DAS28 can classify some patients with active RA solely based on a high tender joint count and poor patient global health score. In such cases, intensified treatment with anti-inflammatory drugs would be expected to yield poorer results than in cases with DAS28 elevation due to a high score for swollen joints and C reactive protein (CRP). Evaluation of central pain sensitisation in patients with few inflammatory indices may be a predictive tool regarding the effect of anti-inflammatory treatment. Computerised pneumatic cuff pressure algometry (CPA) is a method for assessing temporal summation (ie, degree of central sensitisation). The main objective of this study was to examine the prognostic values of pressure pain-induced temporal summation, ultrasound Doppler activity and the interaction between them in relation to treatment response (DAS28-CRP change) in patients with RA initiating any anti-inflammatory therapy. METHOD AND ANALYSIS: 120 participants ≥18 years of age will be recruited. Furthermore, they must be either (1) diagnosed with RA, untreated with disease-modifying antirheumatic drugs for at least 6 months and about to initiate disease-modifying antirheumatic drug treatment or (2) about to begin or switch treatment with any biological drug for their RA. Data (clinical, imaging, blood samples, patient reported outcomes and CPA measurements) will be collected from each participant at baseline and after 4 months of anti-inflammatory treatment. ETHICS AND DISSEMINATION: This study has been approved by the ethics committee for the Copenhagen region (H-4-2013-007). Dissemination will occur through presentations and publication in international peer-reviewed journals.

Repeated intramuscular injections of nerve growth factor induced progressive muscle hyperalgesia, facilitated temporal summation, and expanded pain areas.

Intramuscular injection of nerve growth factor (NGF) is known to induce deep-tissue mechanical hyperalgesia. In this study it was hypothesised that daily intramuscular injections of NGF produce a progressive manifestation of soreness, mechanical hyperalgesia, and temporal summation of pain. In a double-blind placebo-controlled design, 12 healthy subjects were injected on 3 days with NGF into the tibialis anterior muscle and with isotonic saline on the contralateral side. Assessments were performed before and after the injections on days 0, 1, and 2, and repeated on days 3, 6, and 10. The self-perceived muscle soreness was assessed on a Likert scale. Computer-controlled pressure algometry was used to assess the pressure pain thresholds (PPTs). Temporal summation of pain after repeated pressure stimulations was assessed by computer-controlled pressure algometry. The pain distribution following painful pressure stimulation was also recorded. Compared with baseline and isotonic saline, the NGF injections caused (P<0.05): (1) progressively increasing soreness scores from 3 hours after the first injection until day 2, after which it remained increased; (2) decreased PPTs at days 1 to 3; (3) facilitated temporal summation of pressure pain at days 1 to 10; and (4) enlarged pressure-induced pain area after the injection on day 1 to day 6. The daily injections of NGF produced a progressive manifestation of muscle soreness, mechanical hyperalgesia, temporal summation of pressure pain, and pressure-induced pain distribution. These data illustrate that the prolonged NGF application affects peripheral and central mechanisms and may reflect process in musculoskeletal pain conditions.

The cardiac sympathetic co-transmitter galanin reduces acetylcholine release and vagal bradycardia: implications for neural control of cardiac excitability.

The autonomic phenotype of congestive cardiac failure is characterised by high sympathetic drive and impaired vagal tone, which are independent predictors of mortality. We hypothesize that impaired bradycardia to peripheral vagal stimulation following high-level sympathetic drive is due to sympatho-vagal crosstalk by the adrenergic co-transmitters galanin and neuropeptide-Y (NPY). Moreover we hypothesize that galanin acts similarly to NPY by reducing vagal acetylcholine release via a receptor mediated, protein kinase-dependent pathway. Prolonged right stellate ganglion stimulation (10 Hz, 2 min, in the presence of 10 µM metoprolol) in an isolated guinea pig atrial preparation with dual autonomic innervation leads to a significant (p<0.05) reduction in the magnitude of vagal bradycardia (5 Hz) maintained over the subsequent 20 min (n=6). Immunohistochemistry demonstrated the presence of galanin in a small number of tyrosine hydroxylase positive neurons from freshly dissected stellate ganglion tissue sections. Following 3 days of tissue culture however, most stellate neurons expressed galanin. Stellate stimulation caused the release of low levels of galanin and significantly higher levels of NPY into the surrounding perfusate (n=6, using ELISA). The reduction in vagal bradycardia post sympathetic stimulation was partially reversed by the galanin receptor antagonist M40 after 10 min (1 µM, n=5), and completely reversed with the NPY Y(2) receptor antagonist BIIE 0246 at all time points (1 µM, n=6). Exogenous galanin (n=6, 50-500 nM) also reduced the heart rate response to vagal stimulation but had no effect on the response to carbamylcholine that produced similar degrees of bradycardia (n=6). Galanin (500 nM) also significantly attenuated the release of (3)H-acetylcholine from isolated atria during field stimulation (5 Hz, n=5). The effect of galanin on vagal bradycardia could be abolished by the galanin receptor antagonist M40 (n=5). Importantly the GalR(1) receptor was immunofluorescently co-localised with choline acetyl-transferase containing neurons at the sinoatrial node. The protein kinase C inhibitor calphostin (100 nM, n=6) abolished the effect of galanin on vagal bradycardia whilst the protein kinase A inhibitor H89 (500 nM, n=6) had no effect. These results demonstrate that prolonged sympathetic activation releases the slowly diffusing adrenergic co-transmitter galanin in addition to NPY, and that this contributes to the attenuation in vagal bradycardia via a reduction in acetylcholine release. This effect is mediated by GalR(1) receptors on vagal neurons coupled to protein kinase C dependent signalling pathways. The role of galanin may become more important following an acute injury response where galanin expression is increased.

Inhibitory effect of asiatic acid on acetylcholinesterase, excitatory post synaptic potential and locomotor activity.

The asiatic acid, a triterpenoids isolated from Centella asiatica was used to delineate its inhibitory effect on acetylcholinesterase (AChE) properties, excitatory post synaptic potential (EPSP) and locomotor activity. This study is consistent with asiatic acid having an effect on AChE, a selective GABA(B) receptor agonist and no sedative effect on locomotor.

The effect of target-controlled infusion of low-dose ketamine on heat pain and temporal summation threshold.

PURPOSE: We investigated the heat pain threshold (HPT) and temporal summation threshold (TST) before and after target-controlled infusion (TCI) of ketamine with an effect-site concentration (Ce) of 30 and 60 ng/ml. METHODS: Healthy young volunteers (n = 20) were enrolled. A thermode was applied to the volar side of each volunteer's right forearm, and HPT and TST were measured before and after TCI of ketamine. Vital signs and psychedelic effects according to ketamine infusion were also observed before and after TCI of ketamine. RESULTS: Mean HPT after TCI of ketamine with a Ce of 30 and 60 ng/ml did not increase significantly. However, mean TST after TCI of ketamine with a Ce of 30 and 60 ng/ml increased significantly, in a dose-dependent fashion, compared with the value before ketamine TCI. Vital signs showed no significant difference before and after ketamine TCI. The visual analog scale score of psychedelic symptoms was higher with a Ce of 60 ng/ml than with 30 ng/ml. CONCLUSIONS: TCI of ketamine with a Ce of 30 and 60 ng/ml increased TST but not HPT.