Electrical low‐frequency stimulation induces central neuroplastic changes of pain processing in man

Electrical low‐frequency stimulation (LFS) inhibits pain perception and nociceptive processing as shown by psychophysical and electrophysiological means (long‐term depression, LTD). Information regarding central mechanisms involved in LTD induction and maintenance are still missing. This study hypothesizes that electrical LFS induces changes in activation pattern of pain‐related brain areas. Thirty‐two electrophysiological and psychophysical experiments were performed in 16 healthy volunteers. Painful electrical test stimulation (0.125 Hz, 60 pulses) and conditioning LFS (1 Hz, 1200 pulses) were applied by a concentric electrode to the right hand. Test stimulation series were performed before (Pre) and after LFS (Post) or no stimulation period (Control). Volunteers rated pain perception according to a verbal rating scale (0–100). Somatosensory evoked cortical potentials were recorded with 64‐channel electroencephalography. Individual dipole source modeling using CURRY software (Compumedics, Hamburg, Germany) yielded information about dipole location and strength. The strongest decrease in LFS‐induced pain perception was shown after LFS (p < 0.01). Topographic distribution of cortical potentials revealed reproducible negative (N1, N2) and positive (P2) components. Dipole magnitude analysis showed a significant difference between Post LFS and Post Control for P2 (p < 0.01). P2 dipole location analysis yielded a significant posterior (p < 0.05) shift following LTD induction. Thus, data reveal central changes of pain processing after LTD induction. These experiments may help judging the potency of LTD as model for electrostimulation in future analgesic therapy.     

Mechanisms of pain referral in patients with whiplash associated disorder

The aim was to investigate the mechanisms of pain referral in patients with whiplash associated disorder. Pain was induced in 12 controls and 12 patients with whiplash associated disorder by intramuscular electrical stimulation in the infraspinatus muscle and the ipsilateral upper arm, i.e., the area where all subjects perceived referred pain during conditioning stimulation in the infraspinatus muscle. Conditioning stimulation amounted to a pain intensity rated as 2/10 and 4/10. During conditioning stimulation in the infraspinatus muscle, sensitivity to test stimuli was assessed in the referred pain area (i.e., upper arm) and vice versa. Test stimuli consisted of intramuscular electrical stimulation corresponding to innocuous perception threshold, electrical pain threshold, and pain intensities rated as 2/10, 4/10 and 6/10, respectively. Compared to controls, patients with whiplash associated disorder had increased pain sensitivity (p≤0.01) and indicated larger areas of referred pain ((p≤0.003) during stimulation at the infraspinatus muscle; p≤0.03 during stimulation at the upper arm), including proximal referral of pain which was never reported by controls (p≤0.05). During conditioning stimulation in the infraspinatus muscle (4/10) all subjects reported referred pain in the upper arm (corresponding to the test site) and innocuous perception thresholds (p<0.05)(patients) and electrical pain thresholds (p<0.001) (controls) decreased. Conditioning stimulation in the upper arm did not affect sensitivity to test stimuli in the infraspinatus muscle. In conclusion, patients with whiplash associated disorder had increased sensitivity to painful stimulation, reported larger areas of referred pain during the same subjectively painful conditioning stimulation (i.e., lower absolute stimulus intensities), including proximal pain referral which was never seen in controls, indicating aberrant processing of nociceptive input. The perceptual integration of nociceptive stimuli during simultaneous stimulation did not differ between groups suggesting that divergence of nociceptive input from the focal pain area leading to excitation of neurones with projected fields in the referred pain area most likely explains referred pain in both groups alike.     

Differential effects of lidocaine on nerve growth factor (NGF)‐evoked heat‐ and mechanical hyperalgesia in humans

We investigated the effects of a non‐specific sodium channel blocker (lidocaine) on heat pain thresholds and mechanical impact pain at day 7 and 21 after intradermal injection of 1 μg NGF. Measurements were performed in 12 healthy male subjects prior to and 5 min after intradermal injection of 150 μl lidocaine administered at concentrations of 0.01% (～0.4 mM) and 0.1% (～4 mM) to both NGF and control skin sites. NGF caused a maximum reduction of heat pain thresholds at day 7 (NGF 42.6 ± 0.6 vs. 49.4 ± 0.3 °C in control skin). Lidocaine sensitized normal skin for heat pain, but reduced heat hyperalgesia after NGF at day 7 (44.3 ± 0.8 °C, lidocaine 0.1%; p < 0.005). Pain upon supra‐threshold mechanical impact stimulation was increased after NGF at day 7 (VAS 29 + 5) and massively enhanced at day 21 (VAS 64 + 5, p < 0.001). Lidocaine dose‐dependently attenuated mechanically‐induced pain at both control and NGF‐treated sites. Maximum lidocaine effects on mechanical hyperalgesia were recorded at day 21 in NGF skin (pain reduction to VAS 37 ± 4, p < 0.00001). Repetitive impact stimuli caused increasingly more pain at the NGF sites at day 21 and this pain increase was efficiently suppressed by lidocaine 0.1%. Lidocaine differentially affects NGF‐induced mechanical hyperalgesia (analgesic effect) and heat sensitivity of nociceptors (sensitizing effect). These opposing responses may be attributed to block of sodium channels vs. sensitization of TRPV1. NGF‐evoked extreme mechanical impact pain indicates high action potential discharge frequencies, which might be more susceptible to lidocaine block.     

Central sensitization phenomena after third molar surgery: A quantitative sensory testing study

Background: Surgical removal of third molars may carry a risk of developing persistent orofacial pain, and central sensitization appears to play an important role in the transition from acute to chronic pain. Aim: The aim of this study was to investigate sensitization (primarily central sensitization) after orofacial trauma using quantitative sensory testing (QST). Methods: A total of 32 healthy men (16 patients and 16 age‐matched control subjects) underwent a battery of quantitative tests adapted to the trigeminal area at baseline and 2, 7, and 30 days following surgical removal of a lower impacted third molar. Results: Central sensitization for at least one week was indicated by significantly increased pain intensity evoked by intraoral repetitive pinprick and electrical stimulation (p<0.05) including facilitation of temporal summation mechanisms (p<0.05), extraoral repetitive electrical stimulation (p<0.001), significantly more frequent aftersensation in patients (p<0.001), extraoral hyperalgesia due to single pinprick stimulation (p<0.05) and larger pain areas due to intranasal stimulation (p<0.001). Peripheral sensitization was indicated by intraoral hyperalgesia due to single pinprick (p<0.05). Conclusion: We found clear signs of sensitization of the trigeminal nociceptive system for at least one week after the surgery. Our results indicate that even a minor orofacial surgical procedure may be sufficient to evoke signs of both central and peripheral sensitization, which may play a role in the transition from acute to chronic pain in susceptible individuals.     

Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain

Pain hypersensitivity has been consistently detected in chronic pain conditions, but the underlying mechanisms are difficult to investigate in humans and thus poorly understood. Patients with endometriosis pain display enlarged reflex receptive fields (RRF), providing a new perspective in the identification of possible mechanisms behind hypersensitivity states in humans. The primary hypothesis of this study was that RRF are enlarged in patients with musculoskeletal pain. Secondary study end points were subjective pain thresholds and nociceptive withdrawal reflex (NWR) thresholds after single and repeated (temporal summation) electrical stimulation. Forty chronic neck pain patients, 40 chronic low back pain patients, and 24 acute low back pain patients were tested. Electrical stimuli were applied to 10 sites on the sole of the foot to quantify the RRF, defined as the area of the foot from where a reflex was evoked. For the secondary end points, electrical stimuli were applied to the cutaneous innervation area of the sural nerve. All patient groups presented enlarged RRF areas compared to pain-free volunteers (P < .001). Moreover, they also displayed lower NWR and pain thresholds to single and repeated electrical stimulation (P < .001). These results demonstrate that musculoskeletal pain conditions are characterized by enlarged RRF, lowered NWR and pain thresholds, and facilitated temporal summation, most likely caused by widespread spinal hyperexcitability. This study contributes to a better understanding of the mechanisms underlying these pain conditions, and it supports the use of the RRF and NWR as objective biomarkers for pain hypersensitivity in clinical and experimental pain research.     

Spinal long‐term potentiation is associated with reduced opioid neurotransmission in the rat brain

Introduction: Neuronal events leading to development of long‐term potentiation (LTP) in the nociceptive pathways may be a cellular mechanism underlying hyperalgesia. In the present study, we examine if induction of spinal LTP may be associated with functional changes in the supraspinal opioidergic system. The opioid receptors (ORs) play a key role in nociceptive processing and controlling the descending modulatory system to the spinal cord. Methods: Spinal LTP was induced by electrical high‐frequency stimulation (HFS) conditioning applied to the sciatic nerve, and the excitability at spinal level was verified by spinal field potential recordings. To study supraspinal changes in opioid neurotransmission following the same HFS conditioning, we used small animal positron emission tomography (PET) and [¹¹C]Phenethyl‐Orvinol ([¹¹C]PEO). All rats included in the PET study were scanned at baseline and 150 min after HFS, and specific binding was calculated with a reference tissue model. Results: A clear C‐fibre LTP, i.e. increased C‐fibre response and reduced C‐fibre threshold, was observed 150 min after HFS conditioning (t‐test, P<0·05, n = 6). Moreover, increased OR binding, relative to baseline, was observed after the same type of HFS conditioning ipsilaterally in the amygdala, hippocampus, somatosensory cortex and superior colliculus, and bilaterally in the nucleus accumbens, caudate putamen and hypothalamus (paired t‐test, HFS>baseline, P<0·05, n = 8). Conclusions: HFS conditioning of the sciatic nerve resulted in both spinal LTP and functional changes in supraspinal opioidergic signalling. Our findings suggest that induction of spinal LTP may be associated with reduced opioid neurotransmission in brain regions involved in pain modulation and affective‐emotional responses.     

Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype

Background: Carriers of a particular haplotype of the GTP cyclohydrolase gene (GCH1) had less pain after surgery for chronic lumbar radiculopathy and a decreased sensitivity to some experimental mechanical pain stimuli. Ex‐vivo, GCH1 upregulation and BH4 productio after forskolin stimulation were reduced, while baseline BH4 concentrations were not affected. This suggested that the haplotype may mainly exert its modulating function when the GCH1 system is provoked. The present study aimed at (i) testing this hypothesis and (ii) independently reproducing the pain‐decreasing effects of a particular GCH1 haplotype having been previously associated with pain protection. Methods: Experimental pain models with sensitization (local skin inflammation, dermal capsaicin application) and without sensitization (punctate pressure, blunt pressure, thermal and electrical pain) were assessed in 10 homozygous and 22 non‐carriers of the particular GCH1 haplotype reportedly associated with pain protection. GCH1, iNOS upregulation and BH4 production were assessed ex‐vivo in white blood cells after lipopolysaccharide stimulation for 24h. Results: Carriers of the particular GCH1 haplotype addressed in this study had higher thresholds to punctate mechanical pain (von Frey hairs) following local skin inflammation (18.1±11.3 vs. 9±2.8g; p=0.005) and, to a lesser degree, to heat pain following capsaicin sensitization (35.2±0.9 vs. 36.6±2.4°C; p=0.026). In contrast, heat and pressure thresholds and tolerance to electrical stimulation in pain models without sensitization did not differ among the genotypes. GCH1, BH4 and iNOS upregulation in white blood cells after lipopolysaccharide stimulation were decreased in carriers of the GCH1 haplotype, which verified that the genotype groups differed with respect to regulation of the biopterin pathway. Conclusions: This study verifies previous results that decreased GCH1 function or inducibility as a result of genetic polymorphisms protects against pain. This study extents previous results by showing that this pain protection is mainly conferred under conditions of hyperalgesia resulting from sensitization, supporting specific functions of BH4 in relation to particular aspects of pain.     

Study of the effects of various transcutaneous electrical nerve stimulation (TENS) parameters upon the RIII nociceptive and H‐reflexes in humans

Despite over two decades of clinical use, the neurophysiological and anti‐nociceptive effects of transcutaneous electrical nerve stimulation (TENS) have yet to be definitively described. The current study was designed to examine the effect of TENS on the RIII nociceptive reflex elicited in healthy human subjects; the H‐reflex was measured concomitantly to monitor changes in α‐motoneuron excitability. Following approval from the university’s ethical committee, 50 healthy human volunteers (25 male and 25 female) participated in the study. The subjects ranged in age from 18 to 30 years (mean 22, SD 3). Subjects were randomly allocated equally to a control group or one of four TENS groups. In the TENS groups, stimulation was applied for a total of 15 min over the sural nerve in the left leg. Ipsilateral RIII and H‐reflexes were recorded five times during the 45 min experimental period. In addition, subjects also rated pain associated with the RIII reflex using a computerized visual analogue scale (VAS). Statistical analysis using two‐way repeated‐measures ANOVA showed no differences between groups for H‐reflex, RIII reflex nor VAS data. These results suggest that TENS does not significantly affect either of the two reflexes, at least using the parameters and application time in the current study.     

Modulation of the human nociceptive flexion reflex by pleasant and unpleasant odors

The nociceptive withdrawal reflex (NWR), a defensive response that allows withdrawal from a noxious stimulus, is a reliable index of spinal nociception in humans. It has been shown that various kinds of stimuli (emotional, visual, auditory) can modulate the transmission and perception of pain. The aim of the present study was to evaluate, by means of the NWR, the modulatory effect on the spinal circuitry of olfactory stimuli with different emotional valence. The magnitude of the NWR elicited by electrical stimulation of the sural nerve was measured while 18 subjects (9 women, 9 men) smelled pleasant, unpleasant, or neutral odors. The NWR was conditioned by odor probe with interstimulus intervals (ISIs) of 500 ms and 1,500 ms. The magnitude of NWR was significantly greater after the unpleasant odor probe (P <.001) and reduced following the pleasant odor probe (P < .001) at both ISIs. A significant effect of olfactory stimuli on subjective pain ratings were found at both ISIs for pleasant vs unpleasant odors (P < .000), and for both pleasant and unpleasant odors vs neutral and basal conditions (P < .000). No statistical differences in subjective pain ratings at different ISIs were found. Consistent with the notion that NWR magnitude and pain perception can be modulated by stimuli with different emotional valence, these results show that olfactory stimuli, too, can modulate spinal nociception in humans.     

Oral nitric‐oxide donor glyceryl‐trinitrate induces sensitization in spinal cord pain processing in migraineurs: A double‐blind,placebo‐controlled,cross‐over study

Nitric‐oxide donor glyceryl‐trinitrate (GTN) modulates cerebral and spinal regions that are involved in migraine and pain processing. We hypothesized that in migraineurs, the susceptibility to develop a migraine attack after GTN administration should parallel with an high sensitivity to GTN‐induced change in the pain processing at spinal level. We used the temporal summation threshold (TST) of the lower limb nociceptive withdrawal reflex (NWR) and the related pain sensation to study in parallel the time‐course of the effect of the GTN administration on the pain processing at spinal level in migraine and healthy subjects. Twenty‐eight (21 F; 7 M; mean age 34.2±8.2) migraine and 15 (11 F; 4 M; mean age 35.9±8.9) healthy subjects were recruited in a double‐blind, placebo‐controlled, cross‐over trial. Neurophysiological examinations were carried out before (baseline) and 30′, 60′, 120′, 180′ and 240′ after GTN (0.9 mg sublingual) or placebo administration during two different sessions. In migraineurs, GTN administration was associated to a significant facilitation in temporal summation of pain (reduced TST and increased painful sensation) 60′, 120′ and 180′ after drug intake when compared to baseline, to placebo condition and to controls after GTN intake. Furthermore, in migraineurs who developed migraine after GTN, a significant facilitation in temporal summation of pain was detected 60′, 120′ and 180′ after drug intake when compared to patients without clinical response. In migraineurs the susceptibility to develop migraine attack after GTN administration seems to be a specific trait of a subgroup of patients linked to a supersensitivity of the pain system to GTN.     

Activation of anterior cingulate cortex produces inhibitory effects on noxious mechanical and electrical stimuli‐evoked responses in rat spinal WDR neurons

In present study, in vivo electrophysiological techniques were applied to examine the effects of anterior cingulate cortex (ACC) activation on mechanical and electrical stimuli‐evoked responses in rat spinal cord wide‐dynamic‐range (WDR) neurons. We found that bilateral ACC electrical stimulation (100 Hz, 20 V, 20 s) had different effects on neuronal responses to brush, pressure and pinch stimuli (10 s). The brush‐evoked neuronal responses at baseline, post 1 min and post 5 min were 60.8±15.0, 59.2±15.4 and 60.0±19.3 spikes/10 s, respectively (n =10, P >0.05 vs. baseline). The pressure‐evoked neuronal responses at baseline, post 1 min and post 5 min were 77.8±11.9, 38.0±7.8 and 45.8±7.6 spikes/10 s, respectively (n =10, P <0.05 vs. baseline). The pinch‐evoked neuronal responses at baseline, post 1 min and post 5 min were 137.6±16.7, 62.6±17.5 and 68.8±15.0 spikes/10 s, respectively (n =10, P <0.05 vs. baseline). Furthermore, ACC stimulation generated distinct effects on the different components of wind‐up response. The total numbers of late response (LR) and after‐discharge (AD), but not early response (ER), significantly decreased. Collectively, the present study demonstrated that short‐term ACC activation could generate long‐term inhibitory effects on the responses of WDR neurons to noxious mechanical (pressure and pinch) and electrical stimuli. The results indicated that ACC activation could negatively regulate noxious information ascending from spinal cord with long‐term effect, providing potential neuronal substrate for the modulation of ACC activation on nociception.     

Electrical low‐frequency stimulation induces long‐term depression of sensory and affective components of pain in healthy man

Electrical low‐frequency stimulation (LFS) of nociceptive skin afferents reliably induces long‐term depression (LTD) of pain. Recent experiments have assessed the effects of LTD on pain perception by using a simple one‐dimensional rating scale. The psychophysical study investigated the impact of noxious LFS on the sensory and affective aspects of pain perception by multidimensional rating scales. In 20 healthy volunteers, nociceptive fibers of the left hand dorsum were electrically stimulated by a concentric electrode. Test stimulation series (15 stimuli each, 0.125Hz) were performed before (Pre) and after (Post) a conditioning LFS (1Hz, 20min) or no stimulation period (Control). Pain ratings concerning test stimulation and LFS were obtained by multidimensional assessment including Verbal rating scale of perceived stimulus intensity (VRS‐I) and unpleasantness (VRS‐U) and pain perception scale with sensory (SES‐S) and affective items (SES‐A). After the conditioning LFS, VRS‐I, VRS‐U, SES‐S, and SES‐A decreased as compared to Pre series and Control. During conditioning LFS, ratings decreased. Factor analysis of SES‐S revealed sole reduction of superficial sharp pain perception after conditioning LFS in contrast to Control experiment. Perception of deep rhythmic pain decreased over time. Deep constant pain and superficial heat pain were not affected. Electrical test stimulation via concentric electrode evokes sensory as well as affective pain perception. Both components decrease during noxious, conditioning LFS and remain depressed for at least one hour. Reduction of sharp pain points to Aδ fiber mediated LTD. These results stress the analgesic potency of LTD and its possible impact on future therapy in chronic pain.     

Morphine blocks descending pain inhibitory controls in humans.

In man, heterotopic painful thermal conditioning stimuli induce parallel decreases in the spinal nociceptive flexion (RIII) reflex and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve at the ankle. Such phenomena may be related to the diffuse noxious inhibitory controls (DNIC) which were initially described in the rat and subsequently documented in humans. In 9 subjects in the present study, a 2 min application of a moderately noxious temperature (46 degrees C) to the contralateral hand strongly depressed the RIII reflex elicited in the biceps femoris muscle by electrical stimulation of the sural nerve at 1.2 times the reflex threshold. These depressive effects were maximal during the second min of the conditioning period, showing a 80% inhibition of the RIII reflex which gradually recovered to its baseline value 7 min after the end of the conditioning period. Such inhibitory effects were completely blocked 15-26 min after administration of a low dose of morphine hydrochloride (0.05 mg/kg, i.v.). The lifting of the inhibitions was compatible with an action at the opioid receptors since the inhibitions were re-observed 5-16 min after naloxone injection (0.006 mg/kg, i.v.). During all the experimental sessions, heart and respiratory rates remained stable at their control levels. Since it has been shown previously that such a dose of morphine could not have a direct effect within the spinal cord (Willer 1985), it is concluded that this opiate blocks, in a naloxone-reversible fashion, those bulbo-spinal controls which are triggered by heterotopic nociceptive events. Possible implications for hypoalgesia based on the principles of counter-irritation are discussed.     

Within‐session sensitization and between‐session habituation: A robust physiological response to repetitive painful heat stimulation

Habituation and sensitization are important behavioural responses to repeated exposure of painful stimuli. Whereas within‐session response dynamics to nociceptive stimuli is well characterized, little is known about long‐term behaviour due to repetitive nociceptive stimulation. We used a standardized longitudinal heat pain paradigm in 66 healthy participants, 21 patients with chronic low back pain and 22 patients with depression who received daily sessions of 60 suprathreshold heat stimuli (48 °C each) for eight consecutive days. All three groups showed the same response: Repeated painful stimulation over several days resulted in substantially decreased pain ratings to identical painful stimuli. The decreased perception of pain over time was associated with a very robust increase in pain ratings in each single pain session, i.e., all participants sensitized within sessions and habituated between sessions. This uniform pattern was equally present in all examined groups. Chronic pain and depression do not seem to interfere with short‐term sensitization and long‐term habituation in this model of repetitive phasic heat pain.     

MRI tumor characterization using Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M™), a protein‐avid contrast agent

The rationale and objectives were to define the MRI tumor‐characterizing potential of a new protein‐avid contrast agent, Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M?; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg^?1, was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N‐ethyl‐N‐nitrosourea (ENU), 45–250 mg kg^?1. These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two‐compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K^PS) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff–Bloom–Richardson score) and location of necrosis. Eighteen tumor‐bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K^PS and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K^PS and fEV* but not fPV were significantly lower in a group consisting of benign and low‐grade malignant tumors compared with the group of less‐differentiated high‐grade tumors (1.61 ± 0.64 vs 3.37 ± 1.49, p < 0.01; 0.45 ± 0.17 vs 0.78 ± 0.24, p < 0.01; and 0.076 ± 0.048 vs 0.121 ± 0.088, p = 0.24, respectively). It is concluded that the protein‐avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low‐grade malignant lesions from high‐grade cancers. Copyright © 2006 John Wiley & Sons, Ltd.     

Central Pain Sensitization,COMT Val158Met Polymorphism,and Emotional Factors in Fibromyalgia

Neurobiological evidence points to altered central nervous system processing of nociceptive stimuli in fibromyalgia. Enzymes like catechol-O-methyl-transferase (COMT) are involved in the elimination of catecholamines playing a possible role in central sensitization and pain. We used quantitative sensory testing to evidence central sensitization in fibromyalgia patients and test whether COMTVal158Met polymorphism, associated with a reduction in enzyme activity, plays a role in sensitized patients. Pain evaluation and quantitative sensory testing were performed including the spinal nociceptive flexion reflex, a physiologic correlate for the evaluation of central nociceptive pathways. Quality of life and distress questionnaires were used. A total of 137 fibromyalgia patients were assessed and compared to 99 matched controls. Central sensitization (nociceptive flexion reflex <27 mA) was present in 95/134 (71%) patients. Among them, COMT p.Val158Met polymorphism displayed a significant linear “genotype effect” (P = .033), with the Met/Met (mean = 17.8 ± 4.8 mA) and Val/Val (mean = 21.4 ± 4.6 mA) subgroups at the opposite ends of the nociceptive flexion reflex threshold (Met/Met vs Val/Val P = .015) and the Val/Met subgroup (mean = 19 ± 4.9 mA) in between (Val/Met vs Val/Val P = .041). Spontaneous moderate to severe pain was more likely to be associated with COMT Met/Met genotype. Patients showed important emotional distress compared to controls. In sensitized patients, the COMT Met/Met subgroup showed systematically—though not significantly—worse scores for all psychological variables.PerspectiveThe association between COMT p.Val158Met polymorphism and central sensitization in fibromyalgia is essential as it refers to the severity of central sensitization and may be a risk factor for treatment outcome.     

Accelerated outgrowth in cross‐facial nerve grafts wrapped with adipose‐derived stem cell sheets

In this study, we devised a novel cross‐facial nerve grafting (CFNG) procedure using an autologous nerve graft wrapped in an adipose‐derived stem cell (ADSC) sheet that was formed on a temperature‐responsive dish and examined its therapeutic effect in a rat model of facial palsy. The rat model of facial paralysis was prepared by ligating and transecting the main trunk of the left facial nerve. The sciatic nerve was used for CFNG, connecting the marginal mandibular branch of the left facial nerve and the marginal mandibular branch of the right facial nerve. CFNG alone, CFNG coated with an ADSC suspension, and CFNG wrapped in an ADSC sheet were transplanted in eight rats each, designated the CFNG, suspension, and sheet group, respectively. Nerve regeneration was compared histologically and physiologically. The time to reinnervation, assessed by a facial palsy scoring system, was significantly shorter in the sheet group than in the other two groups. Evoked compound electromyography showed a significantly higher amplitude in the sheet group (4.2 ± 1.3 mV) than in the suspension (1.7 ± 1.2 mV) or CFNG group (1.6 ± 0.8 mV; p < .01). Toluidine blue staining showed that the number of myelinated fibers was significantly higher in the sheet group (2,450 ± 687) than in the suspension (1,645 ± 659) or CFNG group (1,049 ± 307; p < .05). CFNG in combination with ADSC sheets, prepared using temperature‐responsive dishes, promoted axonal outgrowth in autologous nerve grafts and reduced the time to reinnervation.     

The effect of trigeminal nociceptive stimulation on blink reflexes and pain evoked by stimulation of the supraorbital nerve

The aim of this study was to investigate the effect of painful conditioning stimuli on pain and blink reflexes to supraorbital nerve stimulation. Electromyograph activity was recorded bilaterally from the orbicularis oculi muscles in 13 normal participants in response to low (2.3 mA) and high-intensity (18.6 mA) electrical stimulation of the left supraorbital nerve before, during and after the application of ice to the left or right temple or immersion of the left hand in ice-water for 60 s. The pain evoked by the high-intensity electrical stimulus was greater during painful conditioning stimulation of the ipsilateral temple than during the recovery period afterwards, and was greater than during painful conditioning stimulation of the contralateral temple. These findings imply that spatial summation of nociceptive signals across different divisions of the trigeminal nerve can heighten pain. However, painful conditioning stimulation, particularly to the right temple, strongly suppressed the R2 component of the blink reflex to the low-intensity stimulus, and also suppressed R2 to the high-intensity stimulus. Thus, an inhibitory influence (e.g. diffuse noxious inhibitory controls) appeared to mask ipsilateral segmental facilitation of R2 during ice-induced headache. This finding contrasts with recent electrophysiological evidence of trigeminal sensitization in migraine.     

Does Threat Enlarge Nociceptive Reflex Receptive Fields?

Threat-induced pain modulation can increase survival by amplifying physiological and behavioral reactions toward danger. Threat can also modulate spinal nociception, suggesting engagement of endogenous top-down circuitry. A unique method to assess spinal nociception is via reflex receptive fields (RRF) associated with the nociceptive withdrawal reflex (NWR, a protective spinally-mediated reflex). The size of nociceptive RRFs can be modulated by top-down circuitry with the enlargement of RRFs related to increased spinal nociception. Threat has been previously shown to enhance pain and spinal nociception, but the relationship between threat and RRFs has not been investigated. The present study investigated this issue in 25 healthy individuals. RRFs were determined from NWRs measured by electromyography of the tibialis anterior following electrocutaneous stimulations. RRFs and pain were assessed during periods in which participants were under threat of unpredictable painful abdominal stimulations and when they were not under threat. Results indicated that threat periods led to significantly higher pain, larger nociceptive RRFs and NWR magnitudes. These findings imply that threat produces changes in protective reflexes related to spinal nociceptive sensitivity and increased pain perception. This is likely mediated by top-down circuitry that enhances dorsal horn nociceptive neurons by enlarging RRFs and amplifying ascending pain signals.PerspectiveThis article presents the enlargement of RRF during periods of threat. The results from this study may help clarify the mechanism underlining emotional modulation of spinal nociception.