Supraspinal Level Research Articles

Supraspinal respiratory plasticity following acute cervical spinal cord injury

Impaired breathing is a devastating result of high cervical spinal cord injuries (SCI) due to partial or full denervation of phrenic motoneurons, which innervate the diaphragm – a primary muscle of respiration. Consequently, people with cervical level injuries often become dependent on assisted ventilation and are susceptible to secondary complications. However, there is mounting evidence for limited spontaneous recovery of respiratory function following injury, demonstrating the neuroplastic potential of respiratory networks. Although many studies have shown such plasticity at the level of the spinal cord, much less is known about the changes occurring at supraspinal levels post-SCI. The goal of this study was to determine functional reorganization of respiratory neurons in the medulla acutely (>4h) following high cervical SCI. Experiments were conducted in decerebrate, unanesthetized, vagus intact and artificially ventilated rats. In this preparation, spontaneous recovery of ipsilateral phrenic nerve activity was observed within 4 to 6h following an incomplete, C2 hemisection (C2Hx). Electrophysiological mapping of the ventrolateral medulla showed a reorganization of inspiratory and expiratory sites ipsilateral to injury. These changes included i) decreased respiratory activity within the caudal ventral respiratory group (cVRG; location of bulbospinal expiratory neurons); ii) increased proportion of expiratory phase activity within the rostral ventral respiratory group (rVRG; location of inspiratory bulbo-spinal neurons); iii) increased respiratory activity within ventral reticular nuclei, including lateral reticular (LRN) and paragigantocellular (LPGi) nuclei. We conclude that disruption of descending and ascending connections between the medulla and spinal cord leads to immediate functional reorganization within the supraspinal respiratory network, including neurons within the ventral respiratory column and adjacent reticular nuclei.

Palmitoylethanolamide Reduces Neuropsychiatric Behaviors by Restoring Cortical Electrophysiological Activity in a Mouse Model of Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) represents a major public health problem, which is associated with neurological dysfunction. In severe or moderate cases of TBI, in addition to its high mortality rate, subjects may encounter diverse behavioral dysfunctions. Previous reports suggest that an association between TBI and chronic pain syndromes tends to be more common in patients with mild forms of brain injury. Despite causing minimal brain damage, mild TBI (mTBI) often leads to persistent psychologically debilitating symptoms, which can include anxiety, various forms of memory and learning deficits, and depression. At present, no effective treatment options are available for these symptoms, and little is known about the complex cellular activity affecting neuronal activity that occurs in response to TBI during its late phase. Here, we used a mouse model to investigate the effect of Palmitoylethanolamide (PEA) on both the sensorial and neuropsychiatric dysfunctions associated with mTBI through behavioral, electrophysiological, and biomolecular approaches. Fourteen-day mTBI mice developed anxious, aggressive, and reckless behavior, whilst depressive-like behavior and impaired social interactions were observed from the 60th day onward. Altered behavior was associated with changes in interleukin 1 beta (IL-1β) expression levels and neuronal firing activity in the medial prefrontal cortex. Compared with vehicle, PEA restored the behavioral phenotype and partially normalized the biochemical and functional changes occurring at the supraspinal level. In conclusion, our findings reveal some of the supraspinal modifications responsible for the behavioral alterations associated with mTBI and suggest PEA as a pharmacological tool to ameliorate neurological dysfunction induced by the trauma.

Effect of grouped ST36 or RN12 on gastric motility and sensation

Objective: To investigate the effects of paired ST36 and RN12 acupuncture stimulation on gastric motility and the firing rate of responsible neurons in anesthetized rats. Methods: Using electrophysiological methods, we measured the effects of acupuncture at RN12, ST36, or RN12+ST36 on gastric motility as well as nerve discharges from the gastric sympathetic, vagal nerve, and wide dynamic range (WDR) neurons in the spinal dorsal horn T7-9 in anesthetized rats. Results: 1) Acupuncture at RN12 inhibited gastric motility (83.84±4.49)% and vagal nerve discharge (65.64±5.67)%, but promoted sympathetic nerve activity (243.70±40.67)%; acupuncture at ST36 induced opposing effects on gastric motility (111.31±2.01)% and vagal nerve discharge (166.98±15.92)%. Interestingly, acupuncture at RN12+ST36 together yielded effects similar to that of acupuncture at RN12 alone (93.59±2.05)%, (54.52±7.12)%. 2) WDR neuron discharges induced by gastric distension were inhibited by acupuncture at RN12 (194.56 ± 18.79)%. However, acupuncture at ST36 induced a more significant inhibitory effect. Conclusion: Acupuncture at RN12 inhibits gastric motility by activation of the sympathetic reflex at the spinal level; acupuncture at ST36 promotes gastric motility by activation of the parasympathetic reflex at the supraspinal level, and acupuncture at RN12+ST36 produces a similar decrease in gastric motility as RN12 stimulation alone. Both acupoints decrease the effect of noxious gastric distention on WDR neuron activity, but paired RN12+ST36 stimulation does not significantly affect WDR neuron discharge.

The Effectiveness of Intravenous Dexmedetomidine on Perioperative Hemodynamics, Analgesic Requirement, and Side Effects Profile in Patients Undergoing Laparoscopic Surgery Under General Anesthesia.

Background:There is an upward surge in the use of laparoscopic surgeries due to various advantages when compared to open surgeries. Major advantages are, due to small incisions which are cosmetically acceptable and most of them are now daycare procedures. Problem of economic burden and hospital bed occupancy has been overcome with laparoscopic surgeries. All these advantages are not free from disadvantages, as hemodynamic changes such as hypertension; tachycardia and other surgical-related complications are commonly observed intraoperatively. Dexmedetomidine is one of the α2 agonist drugs which acts at both supraspinal and spinal level and modulate the transmission of nociceptive signals in the central nervous system. The basic effect of dexmedetomidine on the cardiovascular system is to decrease the heart rate and systemic vascular resistance with additional feature of opioid sparing effect. This drug has become an ideal adjuvant during general anesthesia, especially when stress is expected. Hence, the drug was studied in laparoscopic surgeries.Aims and Objectives:(a) To study the effect of dexmedetomidine on hemodynamic parameters during perioperative period in patients undergoing laparoscopic surgery. (b) To study the postoperative sedation score and analgesic requirement. (c) To study the side effect profile of dexmedetomidine.Settings and Design:Randomized double blind controlled trial.Subjects and Methods:After obtaining the Institutional Ethical Clearance, the study was conducted. Forty patients of American Society of Anesthesiologists Class I and II were enrolled in this randomized study. The patients were randomly divided into two groups; group normal saline (NS) and group dexmedetomidine. Patient received either NS or dexmedetomidine in group NS and group dexmedetomidine, respectively, depending upon the allocation. The infusion rate was adjusted according to; loading dose (1 μg/kg) over 10 min and maintenance dose (0.5 μg/kg/h) and perioperative hemodynamics was recorded. Routine general anesthesia was administered in all the patients with conventional technique without deviating from institutional protocols. Postoperatively, Rasmsay sedation score, time taken for request of first analgesic dose, and side effects if any were recorded.Statistical Analysis Used:The categorical factors are represented by the number and frequency (%) of cases. The continuous variables are represented by measures of central frequency and standard deviation. The statistical analysis was done by using unpaired t-test and Chi-square. P < 0.05 was considered statistically significant.Results:Significant hemodynamic changes are observed in NS group during laryngoscopy, intubation, during pneumoperitoneum formation, and during extubation. Hemodynamic stress response in dexmedetomidine group was significantly attenuated. Analgesic requirement during postoperative 24 h were much less in dexmedetomidine group when compared to NS group. No significant side effects were noted except for bradycardia; which was observed in two cases of dexmedetomidine group.Conclusion:Dexmedetomidine infusion in the dose of 1 μg/kg body weight as bolus over 10 min and 0.5 μg/kg/h intraoperatively as maintenance dose controlled the hemodynamic stress response in patients undergoing laparoscopic surgery. Use of dexmedetomidine extends the pain free period postoperatively and thereby reducing total analgesic requirement. Thus, dexmedetomidine can be utilized as an ideal anesthetic adjuvant during laparoscopic surgeries.

Hyperthermia and supraspinal fatigue.

Hyperthermia and supraspinal fatigue.

Changes in Corticospinal and Spinal Excitability to the Biceps Brachii with a Neutral vs. Pronated Handgrip Position Differ between Arm Cycling and Tonic Elbow Flexion.

The purpose of this study was to examine the influence of neutral and pronated handgrip positions on corticospinal excitability to the biceps brachii during arm cycling. Corticospinal and spinal excitability were assessed using motor evoked potentials (MEPs) elicited via transcranial magnetic stimulation (TMS) and cervicomedullary-evoked potentials (CMEPs) elicited via transmastoid electrical stimulation (TMES), respectively. Participants were seated upright in front on arm cycle ergometer. Responses were recorded from the biceps brachii at two different crank positions (6 and 12 o’clock positions relative to a clock face) while arm cycling with neutral and pronated handgrip positions. Responses were also elicited during tonic elbow flexion to compare/contrast the results to a non-rhythmic motor output. MEP and CMEP amplitudes were significantly larger at the 6 o’clock position while arm cycling with a neutral handgrip position compared to pronated (45.6 and 29.9%, respectively). There were no differences in MEP and CMEP amplitudes at the 12 o’clock position for either handgrip position. For the tonic contractions, MEPs were significantly larger with a neutral vs. pronated handgrip position (32.6% greater) while there were no difference in CMEPs. Corticospinal excitability was higher with a neutral handgrip position for both arm cycling and tonic elbow flexion. While spinal excitability was also higher with a neutral handgrip position during arm cycling, no difference was observed during tonic elbow flexion. These findings suggest that not only is corticospinal excitability to the biceps brachii modulated at both the supraspinal and spinal level, but that it is influenced differently between rhythmic arm cycling and tonic elbow flexion.

Central antinociceptive effect of tapentadol is increased by nitric oxide synthase inhibitors.

Nitric oxide synthases (NOSs) have been shown to participate in the mechanism of the antinociceptive action of tapentadol. The results obtained in this study indicate that tapentadol administered intrathecally at a range of doses (30-100 µg) increased nociceptive thresholds in the Randall-Selitto and tail-flick tests in rats; however, this effect was significant only for the higher doses. After intracerebroventricular administration of tapentadol at the same dose range, an antinociceptive effect was observed only in response to mechanical stimuli. In coadministration studies, L-N-nitro arginine (L-NOArg) - a nonselective NOS inhibitor as well as selective inhibitors: 7-Nitroindazole (7-NI), L-N(1-iminoethyl)lysine (L-NIL) or N-(1-iminoethyl)-L-ornithine (L-NIO) for the respective neuronal, inducible, and endothelial NOSs enhanced the antinociceptive activity of intrathecally administered tapentadol in the Randall-Selitto test and to a lesser extent in the tail-flick test. A similar, although less pronounced effect of intracerebroventricular tapentadol was also observed after previous administration of NOS inhibitors in the Randall-Selitto test, but not in the tail-flick test. In conclusion, neuronal NOS, inducible NOS, and endothelial NOS influence the antinociceptive action of tapentadol at the spinal level and to a much lesser extent at the supraspinal level.

Antinociceptive action of botulinum toxin type A in carrageenan-induced mirror pain.

"Mirror pain" or mirror-image pain (MP) is pain opposite to the side of injury. Mechanism and frequency in humans are not known. There is no consent on therapy. Here we report that unilaterally injected botulinum toxin type A (BT-A) has bilateral effect in experimental MP, thus deserves to be investigated as therapy for this condition. We examined the localization of BT-A's bilateral antinociceptive action in MP induced by 3% carrageenan intramuscular injection in Wistar rats. BT-A was applied peripherally (5U/kg), into ipsilateral or contralateral hind paw pad (i.pl.) and centrally (1U/kg), at spinal (intrathecally, i.t.) or supraspinal (intracisternally, i.c.) level. Additionally, we examined the involvement of central opioid and GABAergic systems, as well as the contribution of peripheral capsaicin-sensitive neurons to BT-A's bilateral antinociceptive effect. Ipsilateral i.pl. and i.t. BT-A reduced the bilateral mechanical sensitivity to von Frey filaments, while contralateral i.pl. and i.c. treatments had no effect on either tested side. Bilateral antinociceptive effect of ipsilateral i.pl. BT-A was prevented by μ-opioid antagonist naloxonazine (1.5μg/10μl) and GABAA antagonist bicuculline (1μg/10μl) if applied at the spinal level, in contrast to supraspinal application of the same doses. Local treatment of sciatic nerve with 2% capsaicin 5days following BT-A i.pl. injection caused desensitization of sciatic capsaicin-sensitive fibers, but did not affect bilateral antinociceptive effect of BT-A and the presence of cleaved SNAP-25 at the spinal cord slices. Present experiments suggest segmental actions of peripheral BT-A at spinal level, which are probably not solely dependent on capsaicin-sensitive neurons.

Effects of 5-HT3 receptor blockade on visceral nociceptive neurons in the ventrolateral reticular field of the rat medulla oblongata

The caudal ventrolateral medullary reticular formation is the first supraspinal level processing visce- ral nociceptive signals. In experiments on rats reactions of neurons of this zone to nociceptive stimulation of large intestine were examined and effects of selective blockade of 5-HT3-receptors on these reactions were assessed. According to the character or responses to nociceptive colorectal stimulation (CRS) the re- corded medullary cells were divided into three groups - excitated, inhibited and indifferent. Intravenous injection of 5-HT3-antagonist granisetron (1 and 2 mg/kg) as well as local application of the substance on medulla surface (1.25 and 2.5 nmole) suppressed dose-dependently background and evoked discharges of the reticular neurons excited by CRS but did not exert so much expressed influence on the cells inhibited by visceral nociceptive stimulation. Spike activity of the group of neurons indifferent to CRS under simi- lar conditions was of 5-HT3-independent character. The results obtained provide evidence that 5-HT3-re- ceptors mediate the facilitating effect of serotonin on the supraspinal transmission of abdominal nocicep- tive stimulus which, partly at least, is realized through selective activation of visceral nociceptive neurons of the medulla. The blocking of this mechanism may underlie the analgesic effect of 5-HT3-antagonists in a abdominal pain syndromes.

Brain structural changes in patients with chronic myofascial pain.

Myofascial trigger points (MTrPs) are a highly prevalent source of musculoskeletal pain. Prolonged ongoing nociceptive input from MTrPs may lead to maladaptive changes in the central nervous system. It remains, however, unknown whether pain from MTrPs is associated with brain atrophy. In addition, stress, which may contribute to the formation of MTrPs, is also known to affect brain structures. Here, we address whether structural brain changes occur in patients with chronic pain originating from MTrPs and whether such changes are related to pain or stress. Voxel-based morphometry was used to compare grey-matter (GM) volumes in 21 chronic pain patients, with MTrPs in the bilateral upper trapezius muscles, with 21 healthy controls. Hyperalgesia was assessed by pressure pain thresholds, and stress was assessed by cortisol levels and anxiety questionnaires. Patients exhibited normal stress levels but lowered pain thresholds. GM atrophy was found in dorsal and ventral prefrontal regions in patients. The GM density of the right dorsolateral prefrontal cortex correlated with pain thresholds in patients, i.e. the more atrophy, the lower pain threshold. GM atrophy was also found in the anterior hippocampus, but the atrophy was neither related to pain nor stress. Patients with chronic myofascial pain exhibit GM atrophy in regions involved in top-down pain modulation and in processing of negative affect. The relationship between the dorsolateral prefrontal cortex and pain thresholds suggests the presence of pain disinhibition. No evidence was found for the involvement of stress. It remains unclear whether the observed atrophy contributes to the development of the chronic pain state or is caused by the ongoing nociceptive input. Chronic myofascial pain, caused by myofascial trigger points, is associated with localized brain atrophy in areas involved in pain processing and modulation, among others. These findings extend previous knowledge about peripheral and spinal changes to the supraspinal level.

Gain control mechanisms in the nociceptive system.

The "gate control theory of pain" of 1965 became famous for integrating clinical observations and the understanding of spinal dorsal horn circuitry at that time into a testable model. Although it became rapidly clear that spinal circuitry is much more complex than that proposed by Melzack and Wall, their prediction of the clinical efficacy of transcutaneous electrical nerve stimulation and spinal cord stimulation has left an important clinical legacy also 50 years later. In the meantime, it has been recognized that the sensitivity of the nociceptive system can be decreased or increased and that this "gain control" can occur at peripheral, spinal, and supraspinal levels. The resulting changes in pain sensitivity can be rapidly reversible or persistent, highly localized or widespread. Profiling of spatio-temporal characteristics of altered pain sensitivity (evoked pain to mechanical and/or heat stimuli) allows implications on the mechanisms likely active in a given patient, including peripheral or central sensitization, intraspinal or descending inhibition. This hypothesis generation in the diagnostic process is an essential step towards a mechanism-based treatment of pain. The challenge now is to generate the rational basis of multimodal pain therapy algorithms by including profile-based stratification of patients into studies on efficacy of pharmacological and nonpharmacological treatment modalities. This review outlines the current evidence base for this approach.

Pain regulation of endokinin A/B or endokinin C/D on chimeric peptide MCRT in mice.

The present study focused on the interactive pain regulation of endokinin A/B (EKA/B, the common C-terminal decapeptide in EKA and EKB) or endokinin C/D (EKC/D, the common C-terminal duodecapeptide in EKC and EKD) on chimeric peptide MCRT (YPFPFRTic-NH2, based on YPFP-NH2 and PFRTic-NH2) at the supraspinal level in mice. Results demonstrated that the co-injection of nanomolar EKA/B and MCRT showed moderate regulation, whereas 30 pmol EKA/B had no effect on MCRT. The combination of EKC/D and MCRT produced enhanced antinociception, which was nearly equal to the sum of the mathematical values of single EKC/D and MCRT. Mechanism studies revealed that pre-injected naloxone attenuated the combination significantly compared with the equivalent analgesic effects of EKC/D alone, suggesting that EKC/D and MCRT might act on two totally independent pathways. Moreover, based on the above results and previous reports, we made two reasonable hypotheses to explain the cocktail-induced analgesia, which may potentially pave the way to explore the respective regulatory mechanisms of EKA/B, EKC/D, and MCRT and to better understand the complicated pain regulation of NK1 and μ opioid receptors, as follows: (1) MCRT and endomorphin-1 possibly activated different μ subtypes; and (2) picomolar EKA/B might motivate the endogenous NPFF system after NK1 activation.

Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance

Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.

A common neural element receiving rhythmic arm and leg activity as assessed by reflex modulation in arm muscles.

Neural interactions between regulatory systems for rhythmic arm and leg movements are an intriguing issue in locomotor neuroscience. Amplitudes of early latency cutaneous reflexes (ELCRs) in stationary arm muscles are modulated during rhythmic leg or arm cycling but not during limb positioning or voluntary contraction. This suggests that interneurons mediating ELCRs to arm muscles integrate outputs from neural systems controlling rhythmic limb movements. Alternatively, outputs could be integrated at the motoneuron and/or supraspinal levels. We examined whether a separate effect on the ELCR pathways and cortico-motoneuronal excitability during arm and leg cycling is integrated by neural elements common to the lumbo-sacral and cervical spinal cord. The subjects performed bilateral leg cycling (LEG), contralateral arm cycling (ARM), and simultaneous contralateral arm and bilateral leg cycling (A&L), while ELCRs in the wrist flexor and shoulder flexor muscles were evoked by superficial radial (SR) nerve stimulation. ELCR amplitudes were facilitated by cycling tasks and were larger during A&L than during ARM and LEG. A low stimulus intensity during ARM or LEG generated a larger ELCR during A&L than the sum of ELCRs during ARM and LEG. We confirmed this nonlinear increase in single motor unit firing probability following SR nerve stimulation during A&L. Furthermore, motor-evoked potentials following transcranial magnetic and electrical stimulation did not show nonlinear potentiation during A&L. These findings suggest the existence of a common neural element of the ELCR reflex pathway that is active only during rhythmic arm and leg movement and receives convergent input from contralateral arms and legs.

Depletion of norepinephrine of the central nervous system Down-regulates the blood glucose level in d-glucose-fed and restraint stress models

DSP-4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] is a neurotoxin that depletes norepinephrine. The catecholaminergic system has been implicated in the regulation of blood glucose level. In the present study, the effect of DSP-4 administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on blood glucose level was examined in d-glucose-fed and restraint stress mice models. Mice were pretreated once i.c.v. or i.t. with DSP-4 (10–40μg) for 3days, and d-glucose (2g/kg) was fed orally. Blood glucose level was measured 0 (prior to glucose feeding or restraint stress), 30, 60, and 120min after d-glucose feeding or restraint stress. The i.c.v. or i.t. pretreatment with DSP-4 attenuated blood glucose level in the d-glucose-fed model. Plasma corticosterone level was downregulated in the d-glucose-fed model, whereas plasma insulin level increased in the d-glucose-fed group. The i.c.v. or i.t. pretreatment with DSP-4 reversed the downregulation of plasma corticosterone induced by feeding d-glucose. In addition, the d-glucose-induced increase in plasma insulin was attenuated by the DSP-4 pretreatment. Furthermore, i.c.v. or i.t. pretreatment with DSP-4 reduced restraint stress-induced increases in blood glucose levels. Restraint stress increased plasma corticosterone and insulin levels. The i.c.v. pretreatment with DSP-4 attenuated restraint stress-induced plasma corticosterone and insulin levels. Our results suggest that depleting norepinephrine at the supraspinal and spinal levels appears to be responsible for downregulating blood glucose levels in both d-glucose-fed and restraint stress models.

Connections from the rat dorsal column nuclei (DCN) to the periaqueductal gray matter (PAG)

Electrical stimulation of the dorsal columns (DCs; spinal cord stimulation; SCS) has been proposed to treat chronic neuropathic pain. SCS may activate a dual mechanism that would affect both the spinal cord and supraspinal levels. Stimulation of DCs or DC nuclei (DCN) in animals where neuropathic pain has been induced causes activation of brainstem centers including the periaqueductal gray (PAG), which is involved in the endogenous pain suppression system. Biotinylated dextran-amine (BDA) was iontophoretically injected into the DCN to analyze the ascending projection directed to the PAG. Separate injections into the gracile nucleus (GrN) and the cuneate nucleus (CunN) showed BDA-positive fibers terminating in different regions of the contralateral PAG. GrN-PAG afferents terminated in the caudal and middle portions of PAG-l, whereas CunN-PAG fibers terminated in the middle and rostral portions of PAG-l. Based on the DCN somatotopic map, the GrN sends information to the PAG from the contralateral hindlimb and the tail and the CunN from the contralateral forelimb, shoulder, neck and ear. This somatotopic organization is consistent with earlier electrophysiological and PAG stimulation studies. These fibers could form part of the DCs-brainstem-spinal cord loop, which may be involved in the inhibitory effects of SCS on neuropathic pain.

Lengthened Cutaneous Silent Period in Fibromyalgia Suggesting Central Sensitization as a Pathogenesis.

The pathogenesis of fibromyalgia (FM) has not been clearly elucidated, but central sensitization, which plays an important role in the development of neuropathic pain, is considered to be the main mechanism. The cutaneous silent period (CSP), which is a spinal reflex mediated by A-delta cutaneous afferents, is useful for the evaluation of sensorimotor integration at the spinal and supraspinal levels. To understand the pathophysiology of FM, we compared CSP patterns between patients with FM and normal healthy subjects. Twenty-four patients with FM diagnosed in accordance with the 1990 American College of Rheumatology classification system and 24 age- and sex-matched healthy volunteers were recruited. The CSP was measured from the abductor pollicis brevis muscle. Demographic data, number of tender points, and visual analog scale and FM impact questionnaire scores were collected. The measured CSP and clinical parameters of the patient and control groups were compared. In addition, possible correlations between the CSP parameters and the other clinical characteristics were analyzed. Mean CSP latencies did not differ between patients (55.50 ± 10.97 ms) and healthy controls (60.23 ± 11.87 ms; p = 0.158), although the mean CSP duration was significantly longer in patients (73.75 ± 15.67 ms) than in controls (63.50 ± 14.05 ms; p = 0.021). CSP variables did not correlate with any clinical variables. The significantly longer CSP duration in FM patients suggests central dysregulation at the spinal and supraspinal levels, rather than peripheral small fiber dysfunction.

T-type calcium channels in neuropathic pain.

Pain is a quite frequent complaint accompanying numerous pathologies. Among these pathological cases, numerous neuropathies are retrieved with identified etiologies (chemotherapies, diabetes, surgeries…) and also more diffuse syndromes such as fibromyalgia. More broadly, pain is one of the first consequences of most inherited diseases. Despite its importance for the quality of life, current pain management is limited to drugs that are either old or with a limited efficacy or that possess a bad risk benefit ratio. As no new pharmacological concept has led to new analgesics in the last decades, the discovery of new medications is needed, and to this aim, the identification of new druggable targets in pain transmission is a first step. Therefore, studies of ion channels in pain pathways are extremely active. This is particularly true with ion channels in peripheral sensory neurons in dorsal root ganglia known how to express unique sets of these channels. Moreover, both spinal and supraspinal levels are clearly important in pain modulation. Among these ion channels, we and others revealed the important role of low voltage-gated calcium channels in cellular excitability in different steps of the pain pathways. These channels, by being activated nearby resting membrane potential, have biophysical characteristics suited to facilitate action potential generation and rhythmicity. In this review, we will present the current knowledge on the role of these channels in the perception and modulation of pain.

Altered Expression of Cytoskeletal and Axonal Proteins in Oxaliplatin-Induced Neuropathy

Background: Oxaliplatin is a platinum compound widely used in the treatment of some solid tumors. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug. This study examined the structural neuronal effects of oxaliplatin treatment in spinal and supraspinal levels. Methods: Protein expression was investigated in the mouse cortex, thalamus, periaqueductal grey (PAG) matter and spinal cord (SC) by Western blotting. Thermal nociception was assessed by the hot plate test. Results: Results indicate a reduction in the levels of growth associated protein-43 (GAP43) in the cortex and SC areas at the end of thermal hyperalgesic response, while a decrease in neurofilament-H (NfH) phosphorylation was observed in the SC on day 21 when the pain-related manifestation reaches the neurotoxic peak. Counteracting phosphorylated NfH content increases in the SC and cortex regions at day 28 as a result of the beginning of neuro-regeneration process. We also revealed that the levels of HuD, a neuronal-specific RNA-binding protein, decreased, demonstrating the same temporal and regional expression pattern of GAP43. Oxaliplatin chronic treatment induced a region-specific upregulation of γ isoform of protein kinase C (PKC) within thalamus and PAG, and the administration of a PKC inhibitor suggests that PKC activity in these brain regions must be required to maintain the thermal hyperalgesic state. Conclusions: These results suggest that changes in the protein levels of the regulatory and structural proteins are due to oxaliplatin-induced neurotoxicity and imply that there is a direct link between structural changes in the central nervous system and chemotherapy-induced neurotoxicity.

Changes in synaptic transmission of substantia gelatinosa neurons after spinal cord hemisection revealed by analysis using invivo patch-clamp recording.

BackgroundAfter spinal cord injury, central neuropathic pain develops in the majority of spinal cord injury patients. Spinal hemisection in rats, which has been developed as an animal model of spinal cord injury in humans, results in hyperexcitation of spinal dorsal horn neurons soon after the hemisection and thereafter. The hyperexcitation is likely caused by permanent elimination of the descending pain systems. We examined the change in synaptic transmission of substantia gelatinosa neurons following acute spinal hemisection by using an in vivo whole-cell patch-clamp technique.ResultsAn increased spontaneous action potential firings of substantia gelatinosa neurons was detected in hemisected rats compared with that in control animals. The frequencies and amplitudes of spontaneous excitatory postsynaptic currents and of evoked excitatory postsynaptic currentss in response to non-noxious and noxious stimuli were not different between hemisected and control animals. On the contrary, the amplitude and frequency of spontaneous inhibitory postsynaptic currents of substantia gelatinosa neurons in hemisected animals were significantly smaller and lower, respectively, than those in control animals (P < 0.01). Large amplitude and high-frequency spontaneous inhibitory postsynaptic currents, which could not be elicited by mechanical stimuli, were seen in 44% of substantia gelatinosa neurons in control animals but only in 17% of substantia gelatinosa neurons in hemisected animals. In control animals, such large amplitude spontaneous inhibitory postsynaptic currents were suppressed by spinal application of tetrodotoxin (1 µM). Cervical application of lidocaine (2%, 10 µl) also inhibited such large amplitude of inhibitory postsynaptic currents. The proportion of multi-receptive substantia gelatinosa neurons, which exhibit action potential firing in response to non-noxious and noxious stimuli, was much larger in hemisected animals than in control animals.ConclusionsThese suggest that substantia gelatinosa neurons receive tonic inhibition by spinal inhibitory interneurons which generate persistent action potentials. Spinal hemisection results in hyperexcitation of substantia gelatinosa neurons at least in part by eliminating the tonic descending control of spinal inhibitory interneurons from supraspinal levels.