Abnormal cerebral processing of oesophageal stimuli in patients with noncardiac chest pain (NCCP)

In noncardiac chest pain (NCCP), altered visceral perception may result from abnormal cerebral processing of sensory input rather than abnormalities of afferent pathways. However, the interactions between symptoms, autonomic function and oesophageal stimuli are poorly studied. Oesophageal stimulation elicits reproducible cortical evoked potentials [CEP] and modulates heart rate variability via vagal pathways, as visible on power spectrum analysis of heart rate variability [PS-HRV]. These methods are increasingly used to study the function of visceral afferent neural pathways in human. The aim of this study was to compare EP and PS-HRV during oesophageal stimuli in NCCP and controls. Twelve healthy volunteers (one female, 11 male; aged 24-51 years; mean 32 +/- 8 years), and eight NCCP patients (three female, five male; age range 26-58, mean 40.5 +/- 10 years) were studied. Electrical oesophageal stimulation (EOS; 200 microseconds, 0.2 Hz, 25 stimuli) was applied to the oesophageal wall 5 cm above the lower oesophageal sphincter (LOS), and perception thresholds (measured in mA) determined. EP responses were recorded using 22 standard electroencephalogram scalp electrodes. Autonomic activity was assessed using PS-HRV, before, during, and after oesophageal stimulation. Measured PS-HRV indices included high frequency (HF; 0. 15-0.5 Hz) and low frequency (LF; 0.06-0.15 Hz) power, respectively, assessing vagal and sympathetic activity, and the LF/HF ratio. EOS perception occurred at lower thresholds in NCCP than in controls (3. 6 +/- 1 vs. 7.8 +/- 2 mA, P < 0.05). EP amplitude was greater (13 +/- 2 vs. 6 +/- 1 microV, P < 0.0001), and latency longer in controls vs. NCCP (191 +/- 7 ms vs. 219 +/- 6 ms, P < 0.001). In NCCP, EOS decreased sympathetic outflow (low frequency peak on PS-HRV) and increased cardiovagal activity (high frequency peak, P < 0.02) to a significantly higher degree in comparison with controls. During EOS, heart rate decreased in NCCP from 68 vs. 62 beats min-1 (P < 0.003) but not in controls. In NCCP patients, EOS was perceived at lower intensities and was associated with a greater cardiovagal reflex response. EP responses associated with EOS were smaller in NCCP than in controls, suggesting that an increased perception of oesophageal stimuli results from an enhanced cerebral processing of visceral sensory input in NCCP, rather than from hyperalgesic responses in visceral afferent pathways.     

Antiallodynic effects of NMDA glycine(B) antagonists in neuropathic pain: possible peripheral mechanisms

NMDA receptors are implicated in central sensitisation underlying chronic pain, and NMDA antagonists have a potential for the treatment of neuropathic pain. Functional NMDA receptors are also present on primary afferents, where they may play a role in pro-nociceptive plasticity. The importance of this mechanism in neuropathic pain remains unclear. In the present work, we have compared in models of chronic pain the effects of NMDA antagonists at the glycine(B) site with different central access. L-701,324 (the centrally active antagonist) and 5,7-dichlorokynurenic acid (5,7-DCK, known to have limited central access) were tested after systemic administration in rats in the formalin test and in two models of neuropathic pain. The ability of these compounds to exert central actions (sedation, ataxia) was tested in the open field locomotion test; central NMDA antagonism in vivo was tested in anaesthetised rats on responses of spinal cord neurones to iontophoretic NMDA. Both L-701,324 (2.15-21.5 mg/kg i.p.) and 5,7-DCK (10-46.4 mg/kg i.v.) dose-dependently inhibited Phase II of formalin-evoked behaviour. Likewise, both compounds reversed cold allodynia in the chronic constriction injury model and tactile allodynia in animals with spinal nerve ligation. However, only L-701,324 was able to inhibit neuronal responses to NMDA in the antihyperalgesic dose range; 5,7-DCK was inactive on NMDA responses up to 46.4 mg/kg i.v. or 68.1 mg/kg i.p. Consistent with the lack of inhibition of central NMDA-evoked activity, 5,7-DCK did not alter spontaneous behaviour in the open field test, whereas it was significantly inhibited by L-701,324. Thus, peripheral NMDA receptors may substantially contribute to the efficacy of NMDA antagonists in neuropathic pain.     

Oesophageal wall stretch: the stimulus for distension induced oesophageal sensation

Recently, we reported a novel ultrasound technique to assess the biomechanical properties of the oesophagus in humans. To investigate whether the oesophageal sensation induced by oesophageal distension correlates with wall tension, wall stress or wall strain, we studied 20 healthy subjects using a manometry catheter equipped with a high-compliance bag and a high-frequency intraluminal ultrasound probe. Oesophageal distensions were performed by injecting 1-20 mL water into the bag for 20-30 s. Subjects scored the nature (heartburn or chest pain) and severity of sensation in response to distension, before and after atropine (15 microg kg(-1), i.v.). Ultrasound images of oesophagus were digitized and measurements were made to calculate oesophageal wall tension, stress and strain during distensions. Subjects experienced mostly heartburn, not chest pain, in response to oesophageal distension. Oesophageal wall strain and bag pressures correlated best with the oesophageal sensation. Atropine reduced bag pressure but did not affect the distension induced heartburn and chest pain. We conclude that heartburn is a common sensation in response to oesophageal distension in normal subjects. A strong correlation between wall strain and oesophageal sensation suggests that the wall stretch is the stimulus for nociceptive mechanoreceptors of the oesophagus.     

Characterization of cortical potentials evoked by oesophageal balloon distention and acid perfusion in patients with functional heartburn

Oesophageal visceral hypersensitivity is thought to be important in generating symptoms in functional heartburn (FH). However, the neurophysiological mechanisms involved are poorly understood. The aim of this study was to compare the characteristics of oesophageal cortical evoked potentials (CEPs) induced by balloon distension and acid perfusion in FH and controls. We studied 21 FH patients and 12 healthy volunteers. Oesophageal mechanical stimulation was performed using the specially constructed mechanical pump. CEPs were recorded using the 10-20 international system of electroencephalogram recording. Oesophageal distention elicited recognizable, reproducible and muti-peak CEPs. CEP latencies for N1, P1 and N2 components were significantly shorter (P = 0.016, P = 0.003 and P = 0.031, respectively) in FH than in controls before perfusion. Acid perfusion significantly decreased the latencies of N1, P1 and N2 (P = 0.022, P = 0.007 and P = 0.041, respectively) and significantly increased the amplitude of P1-N2 components (P = 0.020) in FH patients, but not in controls. In conclusion, cortical evoked potential responses evoked by oesophageal distention and acid perfusion were greater in FH than in controls, suggesting that dysfunction of visceral neural pathways and/or alterations in cortical processing may produce and mediate oesophageal hypersensitivity in FH. These findings provide the evidence that central sensitization contributes to the development and maintenance of oesophageal hypersensitivity.     

Involvement of peripheral ionotropic glutamate receptors in activation of cutaneous branches of spinal dorsal rami following antidromic electrical stimulation of adjacent afferent nerves in rats

The aim of the present study was to investigate the role of peripheral ionotropic glutamate receptors in the process of signal transmission between adjacent different peripheral sensory nerves. The T9 and T10 cutaneous branches of spinal dorsal rami were dissociated and cut proximally in pentobarbital anesthetized rats. Eighty-seven single afferents from T10 nerve filaments were recorded and characterized by assessing their spontaneous activities. Following 30 s antidromic electrical stimulation (intensity: 1 mA; duration: 0.5 ms; frequency: 20 Hz) of T9 cutaneous branches, the spontaneous activities of Abeta, Adelta and C fibers of T10 nerve were significantly enhanced from 2.00+/-0.34, 2.42+/-0.33, and 2.19+/-0.32 impulses/min to 4.31+/-0.58, 5.22+/-0.55, and 5.27+/-0.69 impulses/min, respectively (n=29 for each type, P<0.05). These enhanced spontaneous discharges of T10 nerve were significantly blocked by local treatment of its receptive field with either N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 or non-NMDA receptor antagonist DNQX (0.1 mM, 10 microl for each drug) (P<0.05). These results suggest that peripheral ionotropic glutamate receptors are involved in the activation of peripheral nerves following the antidromic stimulation of adjacent afferents from different spinal segments. We further provide the direct evidence that neurotransmitters released from adjacent peripheral nerves may also contribute to the occurrence of allodynia as well as secondary hyperalgesia during the pathological nociception.     

Use of gabapentin for attenuation of symptoms following rapid opiate detoxification (ROD)--correlation with neurophysiological parameters--.

Rapid opiate detoxification (ROD) is a technique whereby the opiate-dependent patient is withdrawn acutely, under anesthesia, from the opioid. Following detoxification, patients experience severe back pain and restlessness often accompanied by a restless-leg-syndrome. We evaluated gabapentin given immediately following detoxification to attenuate these symptoms. In addition, we evaluated the use of the somatosensory-evoked potential (SEP) as a parameter to quantitate pain responses. Patients (n=21; mean age 32.5 +/- 7 SD; 12 males, 9 females) underwent ROD with naltrexone (2 x 50 mg) during propofol anesthesia and artificial ventilation (IPPV). Sympathetic overshoot was attenuated by clonidine, and increased bowl movement was managed by continuous i.v. somatostatin. Back pain, restlessness, and restless-leg-syndrome were treated with gabapentin (1200 mg) in the ICU. Efficacy was assessed by the patient's subjective ratings of restlessness (0-4). In addition, measurements of amplitude (microV), latency (ms) of late N100-peak of the somatosensory evoked potential (SEP), and tolerance to an increased electrical nociceptive stimulus (mA) to the forearm were performed. Data were compared to pre-treatment control and to the period shortly after detoxification. From a mean of 8.4 +/- 2.5 microV, N100-peak increased to a mean of 12.3 microV +/- 3.3 (p < 0.005) following opioid detoxification. Gabapentin reduced amplitude height to a mean of 3.5 +/- 1.5 microV. Also, tolerance to nociceptive stimulus, which had dropped to 4.4 mA, increased to 12.5 mA (p < 0.01), while intensity for restlessness and thrashing of limbs dropped from 3.2 to 1.2 (p < 0.05). The sudden displacement of the opiate from its receptor site induced by naltrexone, resulted in a post inhibitory SEP overshoot with an increase in nociceptive afferent volleys, and a lowering in pain threshold. This was associated with back pain, limb thrashing and a restless-leg-syndrome, all of which could be attenuated by gabapentin. The amplitude of late N100-peak parameter appears to be a potential candidate to quantify the increase of nociception in such patients.     

Abnormal visceral perception in patients with functional dyspepsia: use of cerebral potentials evoked by electrical stimulation of the oesophagus

Altered visceral perception is thought to be included in the pathogenesis of functional dyspepsia. However, in previous studies, the assessment of visceral perception has been based solely on patients’ self‐reported symptoms. Cerebral evoked potential (EP), either by mechanical or electrical stimulation (ES) of the visceral organ, is used to evaluate visceral perception via afferent neural pathways. In this study, we investigated the visceral perception in patients with functional dyspepsia by EP to eliminate the possibility of self‐reported bias. EP responses were recorded by oesophageal ES at 37 cm from the nostril in 14 patients with functional dyspepsia and 14 normal healthy control subjects. Threshold levels of perception, peak latencies and peak‐to‐peak amplitudes of EP were evaluated. There was no difference in the sensory threshold between the dyspeptic patients and the control subjects (median 6 mA, range 2–12 mA, vs. 8 mA, range 6–14 mA; Pthinsp;= 0.09). There was a strong trend towards a decreased discomfort threshold in the patients when compared to the control subjects (median 14 mA, range 6–24 mA vs. 20 mA, range 14–26 mA; Pthinsp;= 0.05). The latency of the later EP peak (N2) among the patients (154 ± 4 ms) was significantly shorter than that of the control subjects (171 ± 3 ms, P < 0.01) although there was no difference between the earlier peaks (N1 and P1). There was also no difference in the amplitudes (N1/P1 and P1/N2) of EP between the patients and the control subjects. Half of the patients (seven out of 14) complained of nausea during ES but the control subjects were unaffected. The latency of the first EP peak (N1) in the patients with nausea was significantly shorter (66 ± 3 ms) than that of the patients without nausea (79 ± 4 ms, P < 0.05) or among the control subjects (80 ± 3 ms, P < 0.05). These results suggest that dyspeptic patients may recruit a greater number of fast conducting myelinated nerve fibres that convey visceral afferent impulses to the brain and/or that dyspeptic patients may have an altered central processing of the visceral perception. We conclude that EP recording by oesophageal ES provides an objective measurement of altered visceral perception in patients with functional dyspepsia.     

TNF-alpha expression in painful and nonpainful neuropathies

OBJECTIVE: To determine whether the cytokine tumor necrosis factor alpha (TNF-alpha) acts as a pain mediator in neuropathic pain in humans. BACKGROUND: In animal models, inflammatory cytokines such as TNF-alpha have been shown to facilitate neuropathic pain. METHODS: The expression of TNF-alpha was analyzed immunohistochemically in 20 human nerve biopsy specimens of patients with painful (n = 10) and nonpainful (n = 10) neuropathies. Additionally, serum soluble TNF-alpha receptor I (sTNF-RI) levels were determined in 24 patients with neuropathies, 16 of which were painful and 8 that were painless. RESULTS: Colocalization studies by confocal fluorescence microscopy for S-100 and TNF-alpha showed expression of TNF-alpha in human Schwann cells. Patients with painful neuropathies showed a stronger TNF-alpha immunoreactivity in myelinating Schwann cells relative to the epineurial background staining compared with patients with nonpainful neuropathy (0.949 +/- 0.047 vs 1.010 +/- 0.053, p < 0.05). Although there was no difference in sTNF-RI levels between painful (n = 16) and nonpainful (n = 8) neuropathies (sTNF-RI: 1412 +/- 545 pg/mL vs 1,318 +/- 175 pg/mL), patients with a mechanical allodynia (n = 9) had elevated serum sTNF-RI (1627 +/- 645 pg/mL vs 1233 +/- 192 pg/mL, p < 0.05) compared with patients without allodynia (n = 15). CONCLUSIONS: TNF-alpha expression of human Schwann cells may be up-regulated in painful neuropathies. The elevation of sTNF-RI in patients with centrally mediated mechanical allodynia suggests that systemic sTNF-RI levels may influence central pain processing mechanisms.     

Red nucleus glutamate facilitates neuropathic allodynia induced by spared nerve injury through non‐NMDA and metabotropic glutamate receptors

Previous studies have demonstrated that glutamate plays an important role in the development of pathological pain. This study investigates the expression changes of glutamate and the roles of different types of glutamate receptors in the red nucleus (RN) in the development of neuropathic allodynia induced by spared nerve injury (SNI). Immunohistochemistry indicated that glutamate was constitutively expressed in the RN of normal rats. After SNI, the expression levels of glutamate were significantly increased in the RN at 1 week and reached the highest level at 2 weeks postinjury compared with sham‐operated and normal rats. The RN glutamate was colocalized with neurons, oligodendrocytes, and astrocytes but not microglia under physiological and neuropathic pain conditions. To elucidate further the roles of the RN glutamate and different types of glutamate receptors in the development of neuropathic allodynia, antagonists to N‐methyl‐D‐aspartate (NMDA), non‐NMDA, or metabotropic glutamate receptors (mGluRs) were microinjected into the RN contralateral to the nerve‐injury side of rats with SNI, and the paw withdrawal threshold (PWT) was dynamically assessed with von Frey filaments. Microinjection of the NMDA receptor antagonist MK‐801 into the RN did not show any effect on SNI‐induced mechanical allodynia. However, microinjection of the non‐NMDA receptor antagonist 6,7‐dinitroquinoxaline‐2,3(1H,4H)‐dione or the mGluR antagonist (±)‐α‐methyl‐(4‐carboxyphenyl) glycine into the RN significantly increased the PWT and alleviated SNI‐induced mechanical allodynia. These findings suggest that RN glutamate is involved in regulating neuropathic pain and facilitates the development of SNI‐induced neuropathic allodynia. The algesic effect of glutamate is transmitted by the non‐NMDA glutamate receptor and mGluRs. © 2015 Wiley Periodicals, Inc.     

Identification of the optimal parameters for recording cortical potentials evoked by mechanical stimulation of the human oesophagus

Cortical evoked potentials (CEP) have been recorded in response to both electrical stimulation (ES) and mechanical stimulation (MS) of the oesophagus. While the optimal parameters for recording reproducible oesophageal CEP to ES have recently been established, they have not yet been determined for MS, and reported CEP to MS show considerable variability. This study aimed to identify the optimal parameters required to record reproducible MS induced CEP. CEP were recorded from the vertex (Cz) in six subjects (one female; age range 23-47 years). MS was performed 5 cm above the lower oesophageal sphincter by rapidly inflating a 2-cm long silicone balloon at a frequency of 0.2 Hz. The rise time to maximum inflation was 165 ms. In order to determine the minimum number of stimuli required to produce optimal signal-to-noise quality, we acquired data in runs of 25, 50, 100 and 300 stimuli and to determine the stimulation intensity that produced the shortest latency and the largest amplitude CEP, we averaged four runs of 50 stimuli at five different intensities ranging from sensory threshold to pain. CEP reproducibility was then assessed in three subjects on three separate occasions using parameters determined from these measurements. We found that optimal signal-to-noise quality was achieved by averaging four runs of 50 stimuli; that P1 latency was shortest and P1-N1 amplitude largest at intensities of 75% and pain threshold and that highly reproducible CEP were obtained in all individuals. We conclude that it is possible to obtain highly reproducible oesophageal CEP to MS which can now be compared to those obtained by ES in order to identify which is most suitable for clinical studies.     

Secondary functional properties of lumbar visceral preganglionic neurons

Preganglionic visceral vasoconstrictor (VVC) neurons and motility-regulating (MR) neurons and other visceral preganglionic neurons, which project in the lumbar splanchnic nerves, were analyzed for their segmental distribution, the conduction velocity of their axons, ongoing activity and reflexes elicited by electrical stimulation of visceral afferents in white rami and of somatic afferents in spinal nerves. Identified preganglionic neurons and neurons without ongoing and reflex activity were distributed over segments L1-L5. VVC neurons were distributed over segments L1-L4 and MR neurons over segments L3-L5. VVC axons conducted at 2.8 +/- 2.5 m/s (mean +/- 1 S.D., n = 49), MR axons at 8.1 +/- 4.7 m/s (n = 131). The ongoing activity of VVC neurons was 1.6 +/- 0.7 imp/s (n = 46), that of MR neurons 0.8 +/- 0.7 imp/s (n = 91). There was no correlation between the conduction velocity of preganglionic axons and the rate of ongoing activity for VVC and MR neurons. (4) Electrical stimulation of visceral afferents in white rami and of somatic afferents in spinal nerves elicited short-latency (less than 50 ms) and long-latency (greater than 50 ms) reflexes in practically all VVC neurons, but preferentially short-latency reflexes in only 50 to 60% of the MR neurons. These results show that VVC and MR neurons are not only different in their reflex patterns, elicited by stimulation of visceral receptors and of arterial baro- and chemoreceptors, but also in the 4 properties analyzed in this paper.     

Gastric hypersensitivity induced by oesophageal acid infusion in healthy volunteers

Abstract  Distal oesophageal acid exposure has been shown to increase visceral sensitivity of the proximal oesophagus via central sensitization. Here we evaluated whether acidification of the distal oesophagus also affects the sensorimotor function of the proximal stomach. A gastric barostat study combined with a 30-min acid (HCl 0.15 mol L⁻¹) or saline infusion in the distal oesophagus was performed in 18 healthy volunteers. Gastric and cutaneous sensitivity was assessed before and up to 2 h after the start of infusion. Directly after acid infusion, but not after saline, the threshold for discomfort decreased (–6.4 ± 1.7 vs 0.4 ± 0.4 mmHg; P = 0.028) and distension-induced symptoms increased significantly compared with the baseline (122 ± 49% vs −3 ± 9%). Cutaneous sensitivity remained unaffected by acid infusion. In contrast, when the infused liquid was aspirated 3 cm more distally, at the level of the lower oesophageal sphincter, the effect of acid infusion on gastric sensitivity was abolished and the increase in distension-induced symptoms was reduced (61 ± 24%). Distal oesophageal acid infusion induces visceral hypersensitivity without affecting somatic sensitivity arguing against a similar mechanism of central sensitization as observed in non-cardiac chest pain. As reduction of the acid load to the stomach prevented this effect, our findings indicate that either gastric and/or duodenal acidification is involved. It should be emphasized though that aspiration from distal oesophagus may have attenuated the effect by reducing the acid-exposed area or by reducing the contact time.     

Long‐lasting increased pain sensitivity in rat following exposure to heroin for the first time

Acute dependence, defined as a precipitation of somatic signs by an antagonist, may occur after a single administration of an opiate drug. Because hyperalgesia is a consistent sign of the withdrawal syndrome, we tested the effectiveness of heroin, an opiate used by addicts, to induce pain facilitation even after a first exposure to the drug. In opiate-naive rats, subcutaneous injection of heroin induced analgesia followed by allodynia, a decrease in pain threshold. This latter phenomenon was observed in the absence of noxious stimuli and lasted several days. An N-methyl-d -aspartate (NMDA) receptor antagonist, MK-801 prevented such long-lasting allodynia. These results suggest that allodynia is an early sign reflecting neural plasticity associated with the development of dependence.     

Physiologic properties of human dentate granule cells in slices prepared from epileptic patients.

The neurophysiological properties of human dentate granule cells were studied in hippocampal slices prepared from patients undergoing surgical treatment for medically intractable temporal lobe epilepsy. In 24 neurons which were morphologically identified as dentate granule cells by intracellular staining with biocytin, there were 2 types of synaptic responses to perforant path stimulation: one showed an EPSP-IPSP sequence (n = 10) and the other showed prolonged EPSPs without accompanying hyperpolarizing IPSPs (n = 14). The prolonged EPSPs were markedly retarded by the application of an NMDA receptor antagonist, APV. Membrane properties of neurons showing the different classes of synaptic responses were similar in resting membrane potential (pooled average: -56.2 mV +/- 0.94 SEM) and spike amplitude (pooled average: 65.2 mV +/- 1.69 SEM). However, membrane resistance tended to be lower in neurons with prolonged EPSPs (31.8 M omega +/- 2.63 SEM) than in neurons that showed EPSP-IPSP responses (40.2 +/- 4.33) (P less than 0.05, Fisher). No spontaneous and/or evoked burst firing was observed. These data provide fuller information on the neurophysiological properties of human dentate granule cells in surgically resected epileptogenic hippocampus, implicating a role of NMDA receptor activation in human temporal lobe epilepsy.     

Different cortical organization of visceral and somatic sensation in humans

Sensory stimuli from the visceral domain exhibit perceptual characteristics different from stimuli applied to the body surface. Compared with somatosensation there is not much known about the cortical projection and functional organization of visceral sensation in humans. In this study, we determined the cortical areas activated by non-painful electrical stimulation of visceral afferents in the distal oesophagus, and somatosensory afferents in the median nerve and the lip in seven healthy volunteers using whole-head magnetoencephalography. Stimulation of somatosensory afferents elicited short-latency responses (≈ 20–60 ms) in the primary somatosensory cortex (SI) contralateral (median nerve) or bilateral (lip) to the stimulated side, and long-latency responses (≈ 60–160 ms) bilaterally in the second somatosensory cortex (SII). In contrast, stimulation of visceral oesophageal afferents did not evoke discernible responses in SI but well reproducible bilateral SII responses (≈ 70–190 ms) in close vicinity to long-latency SII responses following median nerve and lip stimuli. Psychophysically, temporal discrimination of successive stimuli became worse with increasing stimulus repetition rates (0.25 Hz, 0.5 Hz, 1 Hz, 2 Hz) only for visceral oesophageal, but not for somatosensory median nerve stimuli. Correspondingly, amplitudes of the first cortical response to oesophageal stimulation emerging in the SII cortex declined with increasing stimulus repetition rates whereas the earliest cortical response elicited by median nerve stimuli (20 ms SI response) remained unaffected by the stimulus frequency. Our results indicate that visceral afferents from the oesophagus primarily project to the SII cortex and, unlike somatosensory afferents, lack a significant SI representation. We propose that this cortical projection pattern forms the neurophysiological basis of the low temporal and spatial resolution of conscious visceral sensation.     

Role of mitochondrial Ca2+ uniporter in remifentanil‐induced postoperative allodynia

Opioid‐induced hyperalgesia (OIH) and allodynia is a well‐known phenomenon and refers to the pain sensitization in patients after prolonged opioid exposure. OIH limits the use of opioids in pain control, but the underlying mechanisms are not fully clear. This study investigated the role of mitochondrial Ca²⁺ uniporter (MCU) in remifentanil (a commonly used opioid analgesic)‐induced allodynia. Using a rat model of OIH, we found that incision‐ and remifentanil‐induced mechanical allodynia were remarkably attenuated by pretreatment with Ru360, a specific MCU antagonist, suggesting a critical role of MCU in both incision‐ and opioid‐induced allodynia. In addition, imaging studies with Rhod‐2 (a mitochondrial Ca²⁺ dye) in spinal tissues demonstrated increased mitochondrial Ca²⁺ level in response to incision and remifentanil infusion, which was attenuated by Ru360. Western blot and immunohistochemistry showed that pNR [phosphorylated N‐methyl‐D‐aspartate (NMDA) receptor] and pERK (phosphorylated extracellular signal‐regulated kinase) are increased during both incision‐induced hyperalgesia and remifentanil‐induced hyperalgesia, and again the increases in pNR and pERK were remarkably attenuated by Ru360. Together, our data demonstrate that MCU plays a critical role in remifentanil‐induced postoperative mechanical allodynia, with NMDA receptor and ERK as possible downstream effectors. Our findings provide novel mechanisms for remifentanil‐induced mechanical allodynia and encourage future studies to examine the mitochondrial Ca²⁺ uniporter as a potential therapeutic target for prevention of OIH.     

The val66met polymorphism of brain‐derived neurotrophic factor is associated with human esophageal hypersensitivity

Background Recent evidence implicates brain‐derived neurotrophic factor (BDNF) in visceral hypersensitivity and pain in functional gastrointestinal disorders. We hypothesized that presence of the val66met polymorphism in the BDNF gene would be linked to increased esophageal sensitivity to electrical stimulation. Methods A total of 39 healthy volunteers (20 males, mean age 30) compliant with inclusion criteria after screening procedures were genotyped for BDNF polymorphisms and completed an Hospital Anxiety and Depression Scale (HADS) questionnaire. Sensory (ST) and pain (PT) thresholds in the proximal (PE) and distal (DE) esophagus were determined using electrical stimuli to a swallowed intraluminal catheter with bipolar electrodes by an investigator blinded to the subjects’ genotype. For comparison, somatic ST and PT (hand and foot) were also tested. HADS scores together with esophageal and somatic thresholds were then correlated with BDNF polymorphism status. Key Results Eleven of 39 (28%) volunteers had at least one Met allele (Met carriers). When compared with Val/Val, Met carriers had lower esophageal PT (Median PT [mA]: Val/Val vs Met carriers, PE; 49.4 vs 44.3, P = 0.033, DE: 63.8 vs 55.4, P = 0.045) with higher proportion of Val/Val subjects in the upper quartile for PT in both PE (P = 0.021) and DE (P = 0.033), yet similar somatic PT (Median PT [mA] Hand; 33.6 vs 38.0, P = 0.22, Foot; 44.7 vs 44.0, P = 0.48). Sensitivity results were independent of anxiety (P = 0.66) and depression (P = 0.33) scores. Conclusions & Inferences val66met BDNF polymorphisms are associated with increased esophageal sensitivity to experimental electrical stimulation. Thus, BDNF genotype may be a useful biomarker for electrical sensitivity in the healthy human esophagus.     

Swallowing disorders in Parkinson's disease

Impairment of swallowing is a common symptom in advanced stage of Parkinson's disease and severe defect of this function may cause aspiration pneumonia, problems with food intake and cachexy. The aim of this study was to assess the reflex and oral, pharyngeal, oesophageal phase of swallowing. Eleven patients with Parkinson's disease and 9 healthy subjects were investigated by electromyography (EMG) and oesophageal scintigraphy. The study demonstrates delayed triggering of swallowing reflex (543 +/- 84 ms in patients with PD vs. 230 +/- 66 ms in controls, p < 0.05) and prolongation of laryngeal movement (1880 +/- 140 ms vs. 1349 +/- 154 ms, p < 0.05). The prolongation of the oesophageal phase of swallowing with predilection to retention of water in lower one/third part of esophagus (12.45 +/- 2.45 s vs. 6.45 +/- 1.18 s, p < 0.001) was observed. The dysphagia limit, that is the maximum amount of water swallowed at once, was also evaluated (all normal subjects are able to swallow 20 ml water or more at once). In the studied patients with Parkinson's disease it was 4.5 +/- 0.86 ml. These results evidently and objectively indicate the presence of swallowing disorders in Parkinson's disease. Dysphagia was observed in all studied patients, although only 8 of them complained about it. In other 3 cases the impairment of swallowing was subclinical and it was connected with prolongation of oesophageal phase.     

Lesions of the dorsal vagal complex abolish increases in meal size induced by NMDA receptor blockade

Rats increase meal size and duration after intraperitoneal injection of MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. This effect depends upon intact vagal fibers, since the antagonist does not increase intake when visceral afferent and efferent pathways have been interrupted by bilateral subdiaphragmatic vagotomy. NMDA receptors have been demonstrated on vagal afferent fibers and on second-order neurons in the medial subnucleus of the solitary tract (NTS), the area postrema (AP), and the dorsal motor nucleus of the vagus. To determine whether neurons in these structures are crucial for NMDA receptor effects on feeding, we examined the effect of MK-801 on intake of 15% sucrose in rats with aspiration lesions of the AP and adjacent NTS. MK-801 (100 microg/kg, i.p.) significantly increased sucrose intake in these lesioned rats compared to sham-lesioned rats (32.3+/-0.1 ml versus 23.3+/-0.1 ml, P<0.001). However, when the AP/NTS aspiration lesions were combined with bilateral electrolytic destruction of the medial NTS and the DMV, lesioned rats consumed nearly the same amount of sucrose after either saline or MK-801 (25.9+/-2.4 ml versus 24.3+/-3. 0 ml; P=0.687). By contrast, sham-lesioned controls ingested significantly more sucrose following MK-801 compared to saline (19. 8+/-1.0 ml versus 13.1+/-0.8 ml, P<0.001). These results suggest that an intact caudomedial NTS and/or DMV are necessary for increases in intake induced by NMDA receptor blockade. While the AP might participate in MK-801-induced enhancement of intake, it is not essential for this effect.