Search

Introduction We investigated the anatomical location of the spinothalamic tract and its thalamocortical pathway (STT) in the subcortical white matter in normal subjects, using diffusion tensor tractography (DTT). Materials and methods The STT was reconstructed using FMRIB software in 40 normal subjects. The most probable locations of the STT were defined as the location on an axial slice of the centrum semiovale (CS), corona radiata (CR), and posterior limb of the internal capsule (PL). Results The STT was located at an average of 62.66% in the anterior to posterior direction along a horizontal line that passed between the anterior and posterior ends of the brain, and an average of 36.29% lateral from the midline in the CS. In the CR, the STT was located at an average of 79.60% in the anterior to posterior direction along the aforementioned horizontal line, and an average of 36.36% lateral from the midline. In the PL, the STT was located at an average of 83.58% in the anterior to posterior direction along a horizontal line that passed the middle point at the genu of the internal capsule and the posterior endpoint of the putamen, and an average of 69.69% lateral from the midline to the lateral end of the putamen. Conclusions We found the precise anatomical location of the STT in the subcortical white matter in the human brain using DTT. We believe that the results of this study will be helpful to clinicians in the neuroscience field.

Cordotomy consists in the discontinuation of the lateral spinothalamic tract (LST) in the anterolateral quadrant of the spinal cord, which aims to reduce the transference of nociceptive information in the dorsal horn of the gray matter of the spinal cord to the somatosensory cortex. The main indication is for patients with terminal cancer that have a low life expectancy. It improves the quality of life by relieving pain. The results are promising and the pain relief rate varies between 69 and 100%. Generally speaking, the complications are mostly temporary and not remarkable.

Objectives We aimed to investigate the conduction velocity of the cold spinal pathway in healthy humans. Methods Using a cold stimulator consisting of micro-Peltier elements that was able to produce steep cooling ramps up to -300°C/s, we recorded cold-evoked potentials after stimulation of the dorsal midline at C5, T2, T6 and T10 vertebral levels and calculated the conduction velocity of the cold spinal pathway. In all participants, we used laser stimulation to deliver painful heat (Aδ-fibres-mediated) and warm (C-fibres-mediated) stimuli to the same sites in order to compare the conduction velocity of the cold spinal pathway with that of the nociceptive and warm spinal pathways. Results Cold stimulation evoked large-amplitude vertex potentials from all stimulation sites. The mean conduction velocity of the cold spinal pathway was 12.0 m/s, which did not differ from that of the nociceptive spinal pathway (10.5 m/s). The mean conduction velocity of the warm spinal pathway was 2.0 m/s. Discussion This study provides previously unreported findings regarding cold spinal pathway conduction velocity in humans that may be useful in the assessment of spinal cord lesions as well as in intraoperative monitoring during spinal surgery. Significance This neurophysiological study provides previously unreported findings on cold spinal pathway conduction velocity in healthy humans. Cold-evoked potentials may represent an alternative to laser-evoked potential recording, useful to assess spinothalamic tract in patients with spinal cord lesions and monitor patients during spinal surgery.

Background Central post-stroke pain (CPSP) can arise after lesions anywhere in the central somatosensory pathways, essentially within the spinothalamic system (STS). Although the STS can be selectively injured in the mesencephalon, CPSP has not been described in pure midbrain infarcts. Methods Of more than 300 CPSP consecutive cases, we describe five patients who developed definite neuropathic pain following lesions circumscribed to the postero-lateral mesencephalon. Results The mesencephalic lesion responsible for pain was always haemorrhagic and always involved the spinothalamic tract (STT), as demonstrated by suppressed laser-evoked potentials in every case, with or without preserved lemniscal function. In three cases the midbrain injury could be ascribed to trauma, presumably from the cerebellar tentorium. As a result of the paucity of sensory symptoms, the pain was considered as 'psychogenic' in two of the patients until electrophysiological testing confirmed STT involvement. Conclusion Postero-lateral midbrain lesions should be added to potential causes of CPSP. Because pain and spinothalamic deficits may be the only clinical sign, and because small lateral midbrain lesions may be difficult to trail with MRI, mesencephalic CPSP can be misdiagnosed as malingering or psychogenic pain for years. Significance Selective spinothalamic injury caused by small lateral midbrain lesions is a very rare cause of central post-stroke pain that can remain undiagnosed for years. It appears to obey to haemorrhagic, sometimes post-traumatic lesions. Sudden development of contralateral burning pain with isolated spinothalamic deficits may be the only localizing sign, which can be easily objectively detected with electrophysiological testing.

Background We report on a patient with a mild traumatic brain injury (TBI) who developed abdominal pain due to spinothalamic tract (STT) injuries revealed by diffusion tensor tractography (DTT). Case presentation A 53-year-old female patient suffered head trauma resulting from a backward fall. While bathing at a public bathhouse, she fell backward and struck the occipital area of her head against the floor. After the head trauma, she experienced pain in the abdomen and in both hands and feet. She underwent evaluations including conventional brain MRI, abdominal and pelvic ultrasonography, and stomach and intestine endoscopy. No abnormality was observed in her brain or abdomen. In addition, her abdominal pain had not been relieved by medical management. When she came to our hospital 4 years after the head trauma, her pain characteristics and severity were as follows: intermittent pain without allodynia or hyperalgesia; squeezing and warm creeping-like pain in the abdomen (visual analog scale score: 7); tingling pain in both hands and feet (visual analog scale score: 7). She was prescribed pregabalin and gabapentin, and her abdominal and limb pain was well-controlled at a tolerable level. On DTT 4 years after head trauma, the upper portion of the spinothalamic tracts (STTs) in both hemispheres showed partial tearing. Discussion and conclusions Injury of the STT was demonstrated by using DTT in a patient who showed abdominal pain that was refractory to medical management following mild TBI. Our results suggest that central pain due to STT injury might be suspected in patients with abdominal pain that is refractory to medical management following TBI.

Painful diabetic neuropathy may associate with nerve morphological plasticity in both peripheral and central nervous system. The aim of this study was to determine numerical changes of myelinated fibers in the spinothalamic tract region and oligodendrocytes in the spinal dorsal horn of rats with painful diabetic neuropathy and the effects of metformin on the above changes. Male Sprague–Dawley rats were randomly allocated into the control group (n = 7), the painful diabetic neuropathy group (n = 6) and the painful diabetic neuropathy treated with metformin group (the PDN + M group, n = 7), respectively. Twenty-eight days after medication, numbers of myelinated fibers in the spinothalamic tract and oligodendrocytes in the spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group, number of myelinated fibers in the spinothalamic tract increased significantly in the painful diabetic neuropathy and PDN + M group, compared to the painful diabetic neuropathy group, number of myelinated fibers decreased in the PDN + M group (P < 0.05). As the oligodendrocyte in the spinal dorsal horn was considered, its number increased significantly in the painful diabetic neuropathy group compared to the control and the PDN + M group (P < 0.05), there was no significant difference between the control and the PDN + M group (P > 0.05). Our results indicate that painful diabetic neuropathy is associated with a serial of morphometric plasticity in the rat spinal cord including the numerical increase of the myelinated fibers in the spinothalamic tract and the oligodendrocytes in the spinal dorsal horn. The analgesic effect of metformin against painful diabetic neuropathy might be related to its adverse effects on the above morphometric plasticity.

Aims Neuropathic pain after spinal cord injury is one of the most difficult clinical problems after the loss of mobility, and pharmacological or neuromodulation therapy showed limited efficacy. In this study, we examine the possibility of pain modulation by a recombinant adeno‐associated virus (rAAV) encoding small‐hairpin RNA against GCH1 (rAAV‐shGCH1) in a spinal cord injury model in which neuropathic pain was induced by a spinothalamic tract (STT) lesion. Methods Micro‐electric lesioning was used to damage the left STT in rats (n = 32), and either rAAV‐shGCH1 (n = 19) or rAAV control (n = 6) was injected into the dorsal horn of the rats at the same time. On postoperative days 3, 7, and 14, we evaluated neuropathic pain using a behavioral test and microglial activation by immunohistochemical staining. Results A pain modulation effect of shGCH1 was observed from postoperative days 3 to 14. The mechanical withdrawal threshold was 13.0 ± 0.95 in the shGCH1 group, 4.3 ± 1.37 in the control group, and 3.49 ± 0.85 in sham on postoperative day 3 (p, Neuropathic pain after spinal cord injury can be modulated bilaterally by deactivating microglial activation after a unilateral injection of rAAV‐shGCH1 into the dorsal horn of a spinothalamic tract‐lesion spinal cord pain model.

Background Previous studies investigated cold-evoked potentials (CEPs) for the assessment of the integrity of cold-mediating A-delta fibres and the spinothalamic tract. Nevertheless, several methodological questions remained unanswered to proceed to clinical application. How do latencies and amplitudes vary between CEPs and contact heat-evoked potentials (CHEPs)? Are there differences between variable and fixed thermode positions or between glabrous and hairy skin? Are CEPs recordable in patients with abnormal cold processing? Methods A total of 16 healthy subjects were tested with CEPs and CHEPs at the face, hand and foot. Variable and fixed thermode positions, hairy and glabrous skin were compared. Three patients with abnormal cold processing were tested with CEPs and quantitative sensory testing. Results Compared to CEPs, CHEPs latencies were significantly longer at all locations, amplitudes were significantly larger at the face and the hand whilst comparable at the foot. CEPs and CHEPs did not differ significantly between variable and fixed thermode positions using inter stimulus intervals of 8-12 s. CEP latencies were increased by around 20% at the glabrous skin. Patients with known abnormal cold processing (central pain, polyneuropathy, Fabry's disease) showed increased N2 latencies as compared to normal controls. Conclusions Inter stimulus intervals of 8-12 s allow the use of a fixed thermode position for reliable CEPs/CHEPs recording. Hairy skin stimulation results in faster latencies as compared to glabrous skin, without influencing EP amplitudes. In patients with abnormal cold processing, CEPs are recordable and increased latencies may be expected as compared to healthy controls and the healthy contralateral side. Significance Cold-evoked potentials are an innovative, non-invasive technique to assess cold detection and processing objectively. This study shows that CEP can be recorded from the hairy and glabrous skin, regardless of using fixed or variable thermode positions. Loss of A-delta fibre function leads to an increased CEP latency, consistent with loss of cold detection in the QST.

ObjectiveTo assess associations between preserved spinal cord tissue quantified by the width of ventral and dorsal tissue bridges and neuropathic pain development after spinal cord injury.MethodsThis retrospective longitudinal study includes 44 patients (35 men; mean (SD) age, 50.05 (18.88) years) with subacute (ie, 1 month) spinal cord injury (25 patients with neuropathic pain, 19 pain-free patients) and neuroimaging data who had a follow-up clinical assessment at 12 months. Widths of tissue bridges were calculated from midsagittal T2-weighted images and compared across groups. Regression analyses were used to identify relationships between these neuroimaging measures and previously assessed pain intensity and pin-prick score.ResultsPin-prick score of the 25 patients with neuropathic pain increased from 1 to 12 months (Δmean=10.08, 95% CI 2.66 to 17.50, p=0.010), while it stayed similar in pain-free patients (Δmean=2.74, 95% CI −7.36 to 12.84, p=0.576). They also had larger ventral tissue bridges (Δmedian=0.80, 95% CI 0.20 to 1.71, p=0.008) at 1 month when compared with pain-free patients. Conditional inference tree analysis revealed that ventral tissue bridges’ width (≤2.1 or >2.1 mm) at 1 month is the strongest predictor for 12 months neuropathic pain intensity (1.90±2.26 and 3.83±1.19, p=0.042) and 12 months pin-prick score (63.84±28.26 and 92.67±19.43, p=0.025).InterpretationLarger width of ventral tissue bridges—a proxy for spinothalamic tract function—at 1 month post-spinal cord injury is associated with the emergence and maintenance of neuropathic pain and increased pin-prick sensation. Spared ventral tissue bridges could serve as neuroimaging biomarkers of neuropathic pain and might be used for prediction and monitoring of pain outcomes and stratification of patients in interventional trials.

We describe a rare midbrain stroke presenting with predominantly sensory symptoms. A 71-year-old woman was hospitalized due to the recurrence of faciobrachial sensory loss. Magnetic resonance imaging showed an infarct involving the right side of the middle portion of midbrain at the level of the inferior colliculus . In our case we tried to make some clinico-anatomical correlations. The main anatomical structures involved were the medial lemniscal tract, the ventral part of the spinothalamic tract and the trigeminothalamic tract. The location of the stroke would suggest there are overlaps between arterial territories of the midbrain. Clinicians should look for midbrain infarcts in cases of pure sensory stroke.

Background Previous studies have reported functional and structural abnormalities in the thalamus and the pars triangularis of the inferior frontal gyrus in patients with insomnia disorder. However, no studies have been conducted on the white-matter tracts between these 2 brain regions. We aimed to compare the white-matter integrity and structure of the left thalamus–pars triangularis tracts between patients with insomnia and controls, and to characterize the relationship between white-matter integrity and clinical features in patients with insomnia. Methods In total, 22 participants with insomnia disorder and 27 controls underwent overnight polysomnography and brain magnetic resonance imaging, and then completed self-report clinical questionnaires and neurocognitive tests for spatial planning. Structural and diffusion measures such as fractional anisotropy, axial diffusivity, radial diffusivity and trace were analyzed in group comparison and correlation analyses. Results The insomnia group showed significantly lower fractional anisotropy (F = 8.647, p = 0.02) and axial diffusivity (F = 5.895, p = 0.038) in the left thalamus–pars triangularis tracts than controls. In patients with insomnia, fractional anisotropy in the tracts was correlated with the results of the Stockings of Cambridge test (r = 0.451, p = 0.034), and radial diffusivity was correlated with Epworth Sleepiness Scale score (r = 0.437, p = 0.042). Limitations Limitations included analyses of limited brain regions and the cross-sectional design. Conclusion The insomnia group showed decreased integrity in the left thalamus–pars triangularis tracts, and integrity was correlated with cognition and daytime sleepiness. These results may imply that insomnia is characterized by disintegration of the white-matter tract between the left thalamus and inferior frontal gyrus.

An experimental study.This study aimed to investigate task-dependent changes in fractional anisotropy (FA) within the spinal cord during painful stimulation.Earlier experiments by Mandl et al (2008, 2013) used non-invasive functional diffusion tensor imaging (fDTI) to detect white matter fibers that were active during functional tasks. In two studies, it was observed that FA of involved white matter tracts exhibited repeatable task-related increases. In this study, we attempted to extend the fDTI work in the spinal cord.Twenty-three healthy, right-handed men (mean age 22 yrs, standard deviation [SD] = 4) were invited to participate in this study. Diffusion-weighted images were collected over spinal levels C2 to T4 during a painful thermal stimulus applied to the left thenar eminence. In order to investigate task-related activity, FA values within the contralateral (right) spinothalamic tract were analyzed using a generalized estimating equations (GEE) procedure. As a control, we also examined activity in the ipsilateral and contralateral corticospinal tracts, which are not considered to be involved in nociception.Significant task-related decreases in FA were observed in the right spinothalamic tract at vertebral levels C2-C5 (Wald X(1) = 17.754, P 0.001). There was no change in control regions at levels C7-T2 of the same tract, which are located below the level of input from dermatome C6, Wald X(1) = 0.185, P = 0.667. Results in all other regions assessed, that is, the left spinothalamic tract and bilateral corticospinal tract, were also not significant (P 0.05).The current findings suggest that task-related changes in FA associated with the transmission of pain signals along the spinal cord can be detected using fDTI. We observed decreased FA values in the contralateral (right) spinothalamic tract following painful stimulation, while no such activity was apparent in control regions.5.

Objective To investigate whether cool-evoked potentials (CEP) elicited by brisk innocuous cooling of the skin could serve as an alternative to laser-evoked potentials (LEP), currently considered as the best available neurophysiological tool to assess the spinothalamic tract and diagnose neuropathic pain. Methods A novel device made of micro-Peltier elements and able to cool the skin at −300 °C/s was used to record CEPs elicited by stimulation of the hand dorsum in 40 healthy individuals, characterize the elicited responses, and assess their signal-to-noise ratio. Various stimulation surfaces (40 mm2 and 120 mm2), cooling ramps (−200 °C/s and −133 °C/s) and temperature steps (20 °C, 15 °C, 10 °C, 5 °C) were tested to identify optimal stimulation conditions. Results CEPs were observed in all conditions and subjects, characterized by a biphasic negative-positive complex maximal at the vertex (Cz), peaking 190–400 ms after stimulus onset, preceded by a negative wave over central-parietal areas contralateral to the stimulated hand. Their magnitude was modulated by stimulation surface, cooling ramp and temperature step. Conclusion Rapid innocuous skin cooling elicits robust CEPs at latencies compatible with the conduction velocity of Aδ-fibers. Significance CEPs can be a complementary tool to the recording of LEPS for assessing the function of small-diameter Aδ-fibers and the spinothalamic tract.

Transient nociceptive stimuli elicit robust phase-locked local field potentials (LFPs) in the human insula. However, these responses are not preferential for nociception, as they are also elicited by transient non-nociceptive vibrotactile, auditory, and visual stimuli. Here, we investigated whether another feature of insular activity, namely gamma-band oscillations (GBOs), is preferentially observed in response to nociceptive stimuli. Although nociception-evoked GBOs have never been explored in the insula, previous scalp electroencephalography and magnetoencephalography studies suggest that nociceptive stimuli elicit GBOs in other areas such as the primary somatosensory and prefrontal cortices, and that this activity could be closely related to pain perception. Furthermore, tracing studies showed that the insula is a primary target of spinothalamic input. Using depth electrodes implanted in 9 patients investigated for epilepsy, we acquired insular responses to brief thermonociceptive stimuli and similarly arousing non-nociceptive vibrotactile, auditory, and visual stimuli (59 insular sites). As compared with non-nociceptive stimuli, nociceptive stimuli elicited a markedly stronger enhancement of GBOs (150–300 ms poststimulus) at all insular sites, suggesting that this feature of insular activity is preferential for thermonociception. Although this activity was also present in temporal and frontal regions, its magnitude was significantly greater in the insula as compared with these other regions.

Background Physical, psychological, and/or social impairment can result after a stroke and can be exacerbated by pain. One type of pain after stroke, central poststroke pain, is believed to be due to primary central nervous system mechanisms. Estimated prevalence of central poststroke pain ranges widely from 8% to 55% of stroke patients, suggesting a difficulty in reliably, accurately, and consistently identifying central poststroke pain. This may be due to the absence of a generally accepted definition. Aim We aimed to clarify the role of thalamic strokes and damage to the spinothalamic pathway in central poststroke pain patients. Also, we aimed to gain a current understanding of anatomic substrates, brain imaging, and treatment of central poststroke pain. Summary of review Two independent reviewers identified 10,144 publications. Based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we extracted data from 23 papers and categorized the articles’ aims into four sections: somatosensory deficits, pathway stimulation, clinical trials, and brain imaging. Conclusions Our systematic review suggests that damage to the spinothalamic pathway is associated with central poststroke pain and this link could provide insights into mechanisms and treatment. Moreover, historical connection of strokes in the thalamic region of the brain and central poststroke pain should be reevaluated as many studies noted that strokes in other regions of the brain have high occurrence of central poststroke pain as well.

Mechanisms of below-level pain are discoverable as neural adaptations rostral to spinal injury. Accordingly, the strategy of investigations summarized here has been to characterize behavioral and neural responses to below-level stimulation over time following selective lesions of spinal gray and/or white matter. Assessments of human pain and the pain sensitivity of humans and laboratory animals following spinal injury have revealed common disruptions of pain processing. Interruption of the spinothalamic pathway partially deafferents nocireceptive cerebral neurons, rendering them spontaneously active and hypersensitive to remaining inputs. The spontaneous activity among these neurons is disorganized and unlikely to generate pain. However, activation of these neurons by their remaining inputs can result in pain. Also, injury to spinal gray matter results in a cascade of secondary events, including excitotoxicity, with rostral propagation of excitatory influences that contribute to chronic pain. Establishment and maintenance of below-level pain results from combined influences of injured and spared axons in the spinal white matter and injured neurons in spinal gray matter on processing of nociception by hyperexcitable cerebral neurons that are partially deafferented. A model of spinal stenosis suggests that ischemic injury to the core spinal region can generate below-level pain. Additional questions are raised about demyelination, epileptic discharge, autonomic activation, prolonged activity of C nocireceptive neurons, and thalamocortical plasticity in the generation of below-level pain. PERSPECTIVE: An understanding of mechanisms can direct therapeutic approaches to prevent development of below-level pain or arrest it following spinal cord injury. Among the possibilities covered here are surgical and other means of attenuating gray matter excitotoxicity and ascending propagation of excitatory influences from spinal lesions to thalamocortical systems involved in pain encoding and arousal.

Rationale: Headache is the most common physical complaint reported by the following traumatic brain injury (TBI). Several studies using diffusion tensor tractography (DTT) have demonstrated that injury of the spinothalamic tract (STT) is a pathogenetic mechanism of central pain following TBI. However, no study of headache due to injury of the STT has been reported. Patient concerns: Patient 1 was a 52-year-old female who suffered head trauma resulting from an in-car traffic crash. While sitting in a passenger seat in a moving vehicle, another vehicle suddenly hit the car from the right side. Her head hit the door and she suffered a flexion-hyperextension-rotation injury. She began to feel headaches in both fronto-parieto-occipital areas approximately 2 weeks after the crash. The characteristics and severity of pain were as follows: constant tingling and intermittent stabbing pain without allodynia or hyperalgesia (visual analogue scale score: 7). Patient 2 was a 50-year-old male who suffered head trauma from a flexion-hyperextension injury that occurred after being hit from behind by a vehicle while driving his car. He began to feel headache in both fronto-parieto-occipital areas the day after the crash: constant tingling pain without allodynia or hyperalgesia (visual analogue scale score: 6). Diagnoses: The patient 1 was diagnosed as mild TBI due to head flexion-hyperextension-rotation injury. The patient 2 was diagnosed as mild TBI due to head flexion-hyperextension injury. Interventions: Clinical assessment and DTT were performed at 5 months (patient 1) and 10 months (patient 2) after the initial injury. Outcomes: On DTTs of patient 1 and 2, the STTs showed narrowing in both hemispheres. In addition, discontinuations at the subcortical white matter were observed in both hemispheres in patient 2. Lessons: Headache due to injury of the STT was diagnosed in patients with mild TBI. Precise diagnosis of central pain from other types of pain is clinically important because the management of central pain is quite different from those for other types of pain. Our results suggest that headache might be ascribed to the injury of the STT in patients with mild TBI. Therefore, we recommend evaluation of the STT using DTT in patients with mild TBI who complain of headache having the characteristics of neuropathic pain.

C-tactile afferents form a distinct channel that encodes pleasant tactile stimulation. Prevailing views indicate they project, as with other unmyelinated afferents, in lamina I-spinothalamic pathways. However, we found that spinothalamic ablation in humans, whilst profoundly impairing pain, temperature and itch, had no effect on pleasant touch perception. Only discriminative touch deficits were seen. These findings preclude privileged C-tactile-lamina I-spinothalamic projections and imply integrated hedonic and discriminative spinal processing from the body.

Rationale: Recent studies have used diffusion tensor tractography (DTT) to demonstrate that central poststroke pain (CPSP) was related to spinothalamic tract (STT) injury in patients with stroke. However, few studies have been reported about delayed-onset CPSP due to degeneration of the STT following a stroke. Patient's concerns: A 57-year-old female patient presented with right hemiparesis after stroke. Two weeks after onset, she did not report any pain. At approximately 6 months after onset, she reported pain in the right arm and leg, and the pain slowly intensified with the passage of time. At 14 months after onset, the characteristics and severity of her pain were assessed to be continuous pain without allodynia or hyperalgesia; tingling and cold-sensational pain in her right whole arm and leg (visual analog scale score: 5). Diagnoses: The patient was diagnosed as the right hemiparesis due to spontaneous thalamic hemorrhage. Interventions: Clinical assessment and diffusion tensor imaging (DTI) were performed 2 weeks and 14 months after onset. Outcomes: She suffered continuous pain in her right whole arm and leg (visual analog scale score: 5). On DTT of the 2-week postonset DTI scans, the configuration of the STT was well-preserved in both hemispheres. However, in contrast to those 2-week postonset results, the 14-month postonset DTT results showed partial tearing and thinning in the left STT. Regardless, both the 2-week and 14-month postonset DTT showed that the left STT passed through the vicinity of the thalamic lesion. Lessons: Diagnostic importance of performing a DTT-based evaluation of the STT in patients exhibiting delayed-onset CPSP following intracerebral hemorrhage.

Functional magnetic resonance imaging of the brain has helped to reveal mechanisms of pain perception in health and disease. Recently, imaging approaches have been developed that allow recording neural activity simultaneously in the brain and in the spinal cord. These approaches offer the possibility to examine pain perception in the entire central pain system and in addition, to investigate cortico-spinal interactions during pain processing. Although cortico-spinal imaging is a promising technique, it bears challenges concerning data acquisition and data analysis strategies. In this review, we discuss studies that applied simultaneous imaging of the brain and spinal cord to explore central pain processing. Furthermore, we describe different MR-related acquisition techniques, summarize advantages and disadvantages of approaches that have been implemented so far and present software that has been specifically developed for the analysis of spinal fMRI data to address challenges of spinal data analysis.

Palliative cervical cordotomy can be performed via percutaneous radiofrequency ablation of the lateral C1-2 spinothalamic tract. This rare procedure can be safe, effective, and advantageous in mitigating medically intractable unilateral extremity pain for selected patients with end-stage cancer. This report reviews the indications, techniques, risks, and potential benefits of cordotomy. We describe our recent experience treating 3 patients with CT-guided C1-2 cordotomy and provide the first characterization of spinal cord diffusion MR imaging changes associated with successful cordotomy.

After lesions of the somatosensory dorsal column (DC) pathway, the cortical hand representation can become unresponsive to tactile stimuli, but considerable responsiveness returns over weeks of post-lesion recovery. The reactivation suggests that preserved subthreshold sensory inputs become potentiated and axon sprouting occurs over time to mediate recovery. Here, we studied the recovery process in 3 squirrel monkeys, using high-resolution cerebral blood volume-based functional magnetic resonance imaging (CBV-fMRI) mapping of contralateral somatosensory cortex responsiveness to stimulation of distal finger pads with low and high level electrocutaneous stimulation (ES) before and 2, 4, and 6 weeks after a mid-cervical level contralateral DC lesion. Both low and high intensity ES of digits revealed the expected somatotopy of the area 3b hand representation in pre-lesion monkeys, while in areas 1 and 3a, high intensity stimulation was more effective in activating somatotopic patterns. Six weeks post-lesion, and irrespective of the severity of loss of direct DC inputs (98%, 79%, 40%), somatosensory cortical area 3b of all three animals showed near complete recovery in terms of somatotopy and responsiveness to low and high intensity ES. However there was significant variability in the patterns and amplitudes of reactivation of individual digit territories within and between animals, reflecting differences in the degree of permanent and/or transient silencing of primary DC and secondary inputs 2 weeks post-lesion, and their spatio-temporal trajectories of recovery between 2 and 6 weeks. Similar variations in the silencing and recovery of somatotopy and responsiveness to high intensity ES in areas 3a and 1 are consistent with individual differences in damage to and recovery of DC and spinocuneate pathways, and possibly the potentiation of spinothalamic pathways. Thus, cortical deactivation and subsequent reactivation depends not only on the degree of DC lesion, but also on the severity and duration of loss of secondary as well as primary inputs revealed by low and high intensity ES.

Pruritus is an unpleasant sensation that evokes the urgent desire to scratch. It is a symptom derived from many nervous system disorders that affects a large population of humans and is treated by a variety of pharmacological agents with variable access. Chronic itch is a huge unmet health problem which affect upward 20% of people worldwide. The mechanisms underlying the chronic pruritus are complex. Studies of the neurobiology, neurophysiology and cellular biology of itch have gradually been clarifying the mechanism of chronic itch both peripherally and centrally. The discussion has been focused on pruriceptive nerves and their receptors as well as the cytokines/chemokines that play major roles in itch induction. Though it is historically hypothesized that pain convey signal generated with the stimuli under high intensity, and itch transduces signal from the same nerves of pain but under low intensity, recently, with the identification of distinct itch specific sensory afferent fibers the theory has twisted the "intensity" to a existence of a complete separation of pain and itch pathways. This review helps to understand the unique properties of itch signaling pathways and their clinical importance of the itch perception and pruritic diseases.

This study reports on patients who showed central pain due to injury of the spinothalamic tract (STT) caused by fall without direct head trauma.Prospective study.Two patients with mild traumatic brain injury (TBI) resulting from a fall were enrolled. Patient 1 was a 21-year-old female who had suffered a pratfall with no history of direct head trauma. She had begun to feel pain in both upper trunk and lower back and the left leg since ~ 5 days after onset: constant tingling and throbbing sensation with allodynia. Patient 2 was a 39-year-old male who had suffered a pratfall without direct head trauma. He had begun to feel pain in both arms and legs since ~ 4 days after the fall: constant tingling and pricking sensation without allodynia or hyperalgesia.On diffusion tensor tractograhpy (DTT) of patient 1, partial tearing of the right STT was observed at the subcortical white matter. On DTT of patient 2, partial tearing at the subcortical white matter was observed in the right STT and partial narrowing at the subcortical white matter was observed in the left STT.This study demonstrated injury of the STT in patients who suffered from central pain following a fall. The results suggest that minor indirect head trauma can cause traumatic axonal injury of the brain.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

OBJECT The aim of this study was to show that microendoscopic guidance using a double-channel technique could be safely applied during percutaneous cordotomy and provides clear real-time visualization of the spinal cord and surrounding structures during the entire procedure. METHODS Twenty-four adult patients with intractable cancer pain were treated by microendoscopic-guided percutaneous radiofrequency (RF) cordotomy using the double-channel technique under local anesthesia. A percutaneous lateral puncture was performed initially under fluoroscopy guidance to localize the target. When the subarachnoid space was reached by the guiding cannula, the endoscope was inserted for visualization of the spinal cord and surrounding structures. After target visualization, a second needle was inserted to guide the RF electrode. Cordotomy was performed by a standard RF method. RESULTS The microendoscopic double-channel approach provided real-time visualization of the target in 91% of the cases. The other 9% of procedures were performed by the single-channel technique. Significant analgesia was achieved in over 90% of the cases. Two patients had transient ataxia that lasted for a few weeks until total recovery. CONCLUSIONS The use of percutaneous microendoscopic cordotomy with the double-channel technique is useful for specific manipulations of the spinal cord. It provides real-time visualization of the RF probe, thereby adding a degree of safety to the procedure.

Chloroquine (CQ) is an antimalarial drug that elicits severe pruritus in black Africans with malaria fever. This acute itching (2-7 days duration) exhibits age dependency and a racial and genetic predilection. CQ itch is non-histaminergic, which makes it both a good model and a tool to probe the mechanisms of chronic itch. This review focuses on recently discovered mechanisms, neuroscience, mediators, and receptors that are implicated in molecular studies of CQ pruritus. CQ pruritus mechanisms are also compared to that of itching following other systemic diseases, such as chronic kidney disease, chronic liver disease, skin disorders, and burns. There are striking similarities between CQ itching pathways and other chronic itch secondary to systemic disease with or without skin lesions, which have not been previously highlighted. Prominent among these are the shared roles of skin, neural and spinal μ opiate receptors, kappa opiate receptor, nitric oxide, serotonin via 5HT1B/D receptors, cytokines, especially interleukins, and tumor necrosis factor. There is elaborate "cross talk" among the diverse mediators and receptors involved in CQ-induced pruritus. CQ also binds to the mas-related G protein coupled receptors MrgprA3/MrgprX1 present in a small proportion (4-5%) of dorsal root ganglion neurons and skin. The mrgprA3 CQ receptors are coupled to PLC-β3 and a chloride channel to initiate skin itch action potentials in C nerve fibers. Mrgpra3/X1 couples to TRPA1 for calcium influx into neuronal cells at noncutaneous sites. Central CQ itch occurs via gastrin-related peptide (GRP) and its receptor (GRPR) in the dorsal spinothalamic tracts, as well as glutamic mediated GRP projection to parabrachial nucleus. The possibility of chronic itch therapy based on personalized medicine, genetics, and transcriptomics or the use of itch "polypill/polycream" are discussed.

Highlights • Innocuous thermal information is a key component of haptic exploration. • Thermal perception is immediate and robust from mouse to man. • Mouse thermosensory system is genetically and optically accessible. • Circuits and coding principles of thermal processing are starting to be elucidated., Thermal information about skin surface temperature is a key sense for the perception of object identity and valence. The identification of ion channels involved in the transduction of thermal changes has provided a genetic access point to the thermal system. However, from sensory specific ‘labeled-lines’ to multimodal interactive pathways, the functional organization and identity of the neural circuits mediating innocuous thermal perception have been debated for over 100 years. Here we highlight points in the system that require further attention and review recent advances using in vivo electrophysiology, cellular resolution calcium imaging, optogenetics and thermal perceptual tasks in behaving mice that have begun to uncover the anatomical principles and neural processing mechanisms underlying innocuous thermal perception.

Background Understanding spinothalamic tract anatomy may improve lesioning and outcomes in patients undergoing percutaneous cordotomy. Objective To investigate somatotopy and anatomical organization of spinothalamic tracts in the human cervical spinal cord. Methods Patients with intractable cancer pain undergoing cordotomy underwent preoperative and postoperative quantitative sensory testing for sharp pain and heat pain on day 1 and 7 after cordotomy. Intraoperative sensory stimulation was performed with computed tomography (CT) imaging to confirm the location of the radiofrequency electrode during cordotomy. Postoperative magnetic resonance (MR) imaging was performed to define the location of the lesion. Results Twelve patients were studied, and intraoperative sensory stimulation combined with CT imaging revealed a somatotopy where fibers from the legs were posterolateral to fibers from the hand. Sharpness detection thresholds were significantly elevated in the area of maximum pain on postoperative day 1 (P = .01). Heat pain thresholds for all areas were not elevated significantly on postoperative day 1, or postoperative day 7. MR imaging confirmed that the cordotomy lesion was in the anterolateral quadrant, and in this location the lesion had a sustained effect on sharp pain but a transient impact on heat pain. Conclusion In the high cervical spinal cord, spinothalamic fibers mediating sharp pain for the arms are located ventromedial to fibers for the legs, and these fibers are spatially distinct from fibers that mediate heat pain.

Background Allodynia and hyperalgesia present after surgical interventions are often a major complain of surgical patients. It is thought that both peripheral and central mechanisms contribute to these symptoms. In this study, the role of peripheral nerve fibres that express transient receptor potential vanilloid 1 (TRPV1) receptors in the activation of spinothalamic tract (STT) and postsynaptic dorsal column (PSDC) neurons was assessed in a model of surgical pain. Methods Spinothalamic tract and PSDC neurons retrogradely labelled from the thalamus and nucleus gracilis were used. Activation of these projection neurons was evaluated after plantar incision as expression of the early gene product, c-Fos protein, in the nuclei of these neurons. Results There was a robust increase in c-Fos immunopositivity in the STT and PSDC neurons, in the control animals after a plantar incision. This increase in c-Fos expression was significantly attenuated in animals in which a single high-concentration capsaicin injection was made intradermally at the incision site 24 h before the surgery. Conclusions Our results suggest that activation of both STT and PSDC neurons is involved in development of pain states present after surgical incision and that TRPV1-containing peripheral nerve fibres are needed for c-Fos expression in these dorsal horn neurons after plantar incision.

Patients with central post-stroke sensory ataxia (CPSA) suffer from not only somatosensory dysfunction but also the ataxic movement disorder of the affected limb. These sensory and motor impairments possibly interfere each other, but such interference is still unclear. We evaluated smoothness of grasp movements in CPSA patients using a kinematic analysis, and verified the effect of somatosensory reference from the intact hand on grasp movements. Eight CPSA patients were enrolled. We recorded their reach-and-pinch movements of both affected and intact hands toward the tip of the 3-cm-diameter vertical bar, using a three-dimensional measurement system. When executing these movements of one hand, the patients simultaneously pinched the same diameter bar as the goal tip (matched-reference condition: Matched-Ref) or the 5-cm-diameter thicker bar (mismatched-reference condition: Mismatched-Ref) by the other hand. The normalized jerk index (i.e., movement smoothness) of the affected hand was disturbed compared with the intact hand. The kinematic data of the finger opening and closing phases were also disturbed. These disturbances were partially improved with Matched-Ref but not Mismatched-Ref of the intact hand. We successfully evaluated the features of CPSA, indicating that the somatosensory reference method could be useful for rehabilitation in sensory ataxia.

Background: Pain is often one of the most debilitating symptoms in patients with advanced oncological disease. Patients with localized pain due to malignancy refractory to medical treatment can benefit from selective percutaneous cordotomy that disconnects the ascending pain fibers in the spinothalamic tract. Objectives: Over the past year, we have been performing percutaneous radiofrequency cordotomy with the use of the O-Arm intraoperative imaging system that allows both 2D fluoroscopy and 3D reconstructed computerized tomography imaging. We present our experience using this technique, focusing on technical nuances and complications. Methods: A retrospective analysis was conducted of all patients who underwent percutaneous cordotomy between March 2016 and March 2017. Results: Nineteen patients underwent percutaneous cordotomy procedures. Two patients developed intraoperative delirium and were unable to tolerate the procedure. In 16 out of 17 completed procedures, we achieved excellent immediate pain relief (94%). At 1 month after operation, 15 of the 17 (88%) patients were pain free, and at 3 months 5 out of 5 patients available for follow-up were still free of their original pain. Mirror pain developed in 6 of the 17 patients (35%), but was mild in 4 of these cases and controlled with medications. We experienced 1 serious complication (6%) of ipsilateral hemiparesis. Conclusion: Percutaneous cordotomy using the O-Arm is safe and effective in the treatment of intractable oncological pain.

The purpose of this study is to demonstrate the potential of diffusion tensor imaging (DTI) to reveal structural mechanisms underlying spinal ablative procedures, including percutaneous radiofrequency cordotomy (PRFC). PRFC is a surgical procedure that produces analgesia through focal ablation of the lateral spinothalamic tract (STT), thereby interrupting the flow of pain information from the periphery to the brain. To date, studies regarding mechanisms of analgesia after PRFC have been limited to postmortem cadaveric dissection and histology. However, with recent advances in DTI, the opportunity has arisen to study the STT non-invasively in vivo. In this technical note, an individual with successful pain relief following unilateral STT PRFC was examined using DTI, with the contralateral STT serving as an internal control. PRFC substantially reduced rostrocaudal directional DTI signal in the STT from the lesion in the cervical spinal cord through the pons and mesencephalon. Our findings confirm that focal ablation and anterograde degeneration accompany the analgesic effects of PRFC. In vivo imaging of the STT with DTI may contribute to surgical targeting for PRFC procedures, better understanding of the therapeutic and untoward effects of PRFC, and a deeper understanding of spinothalamic contributions to nociception.

Riboflavin metabolites are critical components of the mitochondrial electron transport chain. Manole et al. describe the genetics, phenotypes and neuropathology of a large patient series with riboflavin-responsive neuropathy. Using in-vitro and in-vivo models, they reveal mitochondrial dysfunction in the disorder, and validate riboflavin esters as a potential therapeutic strategy., Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column–medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

Aims A patient developed delayed-onset central pain due to degeneration of the spinothalamic tract resulting from degeneration of the ischemic transcallosal fibers, in the aftermath of a corpus callosum (CC) hemorrhage. The detection and diagnosis of these lesions using diffusion tensor tractography are described. Methods A 59-yr-old man underwent conservative management for hemorrhages in the CC and lateral ventricle that resulted from hitting his head against a wall while falling. He began to feel pain in his right upper and lower extremities approximately 1½ yrs after the initial injury. The pain was characterized as constant tingling, numb, and cool sensation without allodynia or hyperalgesia (visual analogue scale score, 5). Results Disruption of transcallosal fibers in the genu and isthmus of the CC was observed on diffusion tensor tractography 1 mo after the initial injury. By 3 yrs, the diffusion tensor tractography showed that transcallosal fibers in the isthmus (67.8%-77.9%) of the CC had disappeared, and the left spinothalamic tract had become thinner. Conclusion The results suggest that central pain can occur without direct injury of the spinothalamic tract and point up the need for evaluation of the spinothalamic tract and transcallosal fibers in patients with a CC lesion who complain of central pain.

To investigate the roles of mu opioid receptors (MORs) in paraventricular nucleus of the hypothalamus (PVN) on ejaculation and its underlying mechanism in the rats, we performed copulation behavioral testing and acute experiments. During the acute experiments, mean arterial pressure (MAP), heart rate (HR), bulbospongiosus muscle-electromyogram (BSM-EMG) and pressure of vas deferens (PVD) were all recorded. The expression levels and distributions of opioid receptors were also assessed in PVN of male rats. Moreover, adeno-associated virus type 1 (AAV1) was microinjected into PVN to demonstrate whether there are direct projections from PVN to lumbar spinothalamic (LSt) cells. We found that microinjection of MOR agonist, D-A1a2-NM9-Phe4-Gly(ol)5enkephalin (DAGO), into the PVN prolonged the intromission latency and inhibited ejaculation (P = 0.0241, P = 0.0473, respectively), while the opposed results appeared in CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, MOR antagonist) group (P = 0.0021, P = 0.0286, respectively). Moreover, DAGO caused a significant decrease in MAP and HR (P = 0.0065, P = 0.0030, respectively), and PVD decreased significantly after DAGO microinjection in PVN (P = 0.0383). CTAP not only blocked the effect of DAGO but also significantly increased MAP, HR and PVD (P = 0.0003, P = 0.0010, P = 0.0074, respectively). Meanwhile, a significant increase was observed in BSM-EMG activity after microinjecting of CTAP (P = 0.0022), accompanied by visible BSM contraction. Additionally, anterograde monosynaptic transneuronal tracer AAV1 labeling revealed that neurons in PVN projected directly to LSt cells in L3-4 spinal cord. These results indicate that MORs in PVN centrally mediate ejaculation by regulating the sympathetic outflow, which may be treated as a therapeutic target for ejaculation disorders in the future.

Central pain is one of the most important complications after spinal cord injury (SCI), and thereby, its treatment raises many challenges. After SCI, in a cascade of molecular events, a marked increase in glutamate at the injury site results in secondary changes which may impact on supraspinal regions, mainly ventroposterolateral (VPL). There is little information about the changes in glutamate metabolism in the VPL and whether it contributes to SCI-related central pain. The present study was performed to evaluate glutamate release in the VPL following electrolytic lesion of spinothalamic tract (STT). A laminectomy was performed at spinal segments of T9-T10 in male rats, and then, unilateral electrolytic lesions were made in the STT. Glutamate concentrations in ipsilateral VPL dialysate were measured by HPLC method at days 3, 7, 14, 21 and 28 post-injury. Tactile pain and motor activity were also examined. Glutamate levels were significantly increased in ipsilateral VPL of spinal-cord-injured rats 2 weeks after SCI and remained high up to day 28 post-surgery. The STT lesions had no marked effect on our measures of motor activity, but there was a significant decrease in paw withdrawal threshold in the hind paws at day 14 post-SCI. These findings suggest that an increased release of glutamate in VPL plays a role in secondary pathologic changes, leading to neuronal hyperexcitation and neuropathic pain after SCI.

Using diffusion tensor tractography, we investigated the anatomical location of medial lemniscus (ML) and spinothalamic tract (STT) at pons. We recruited 47 healthy volunteers. Evaluation of the anatomical location of ML and STT was performed using the highest probabilistic location at the upper, middle, and lower pons. According to findings, MLs were located around the middle to medial one-third, between midline and lateral boundary of pons in the pontine tegmentum and STTs were located posterolaterally to ML.

This study reports on a patient with traumatic brain injury (TBI) with a thalamic lesion in the ventroposterolateral nucleus which was demonstrated by diffusion tensor tractography (DTT) for the spinothalamic tract and its thalamocortical pathway (STP).One patient with TBI and eight normal control subjects were recruited. A 64-year-old woman who had suffered a motor vehicle accident presented with a persisting tingling sensation and pain in her right upper and lower extremities at 3 weeks after onset. The patient showed impaired touch sensation, but normal proprioception. Diffusion tensor imaging was performed at 1 month after onset. Fractional anisotropy (FA) and mean diffusivity were measured using a region of interest method along the STP.DTT showed normal STP integrities as compared with normal controls. However, the FA values of the left STP at the thalamus were more than 2 SD decreased. The diminished FA value of the left STP in the left thalamus seems to indicate injury of the left ventrolateroposterior nucleus. Central pain and impaired touch sensation of right extremities supports the presence of left STP injury at the ventroposterolateral nucleus in this patient.It is believed that DTT for the STP provides a useful means of detecting thalamic injury in TBI.

Oxytocin (OT) secreted by the hypothalamo-spinal projection exerts antinociceptive effects in the dorsal horn. Electrophysiological evidence indicates that OT could exert these effects by activating OT receptors (OTR) directly on dorsal horn neurons and/or primary nociceptive afferents in the dorsal root ganglia (DRG). However, little is known about the identity of the dorsal horn and DRG neurons that express the OTR. In the dorsal horn, we found that the OTR is expressed principally in neurons cell bodies. However, neither spino-thalamic dorsal horn neurons projecting to the contralateral thalamic ventral posterolateral nucleus (VPL) and posterior nuclear group (Po) nor GABaergic dorsal horn neurons express the OTR. The OTR is not expressed in skin nociceptive terminals or in dorsal horn nociceptive fibers. In the DRG, however, the OTR is expressed predominantly in non-peptidergic C-fiber cell bodies, but not in peptidergic or mechanoreceptor afferents or in skin nociceptive terminals. Our results suggest that the antinociceptive effects of OT are mediated by direct activation of dorsal horn neurons and peripheral actions on nociceptive, non-peptidergic C-afferents in the DRG.