Spinal signalling of C-fiber mediated pleasant touch in humans.

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.

Cold-evoked potentials versus contact heat-evoked potentials-Methodological considerations and clinical application.

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.

The neural circuits of thermal perception.

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.

Event-related brain potentials elicited by high-speed cooling of the skin: A robust and non-painful method to assess the spinothalamic system in humans.

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.

Molecular mechanisms of pruritus.

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.

Cold-evoked potentials - Ready for clinical use?

BACKGROUND: Cold-evoked potentials (CEPs) are known to assess the integrity of A-delta fibres and the spinothalamic tract. Nevertheless, the clinical value was not investigated previously. The aim of this study was to measure CEPs in 16 healthy subjects from the face, hand and foot sole and to investigate whether CEPs reliably detect A-delta fibre abnormalities. METHODS: Swift cold stimuli were applied to the skin with a commercially available thermode, which cooled down from 30 to 25 °C in approximately 0.5 s. CEP latencies (N1, N2 and P2) and amplitudes (N1, N2/P2) were recorded with EEG. Reversible A-fibre function loss was induced by applying a selective A-fibre block at the superficial radial nerve. RESULTS: In all 16 subjects CEPs could be recorded from all locations; N2, P2 mean latencies were 276.4 ± 38.9 and 389.8 ± 52.5 (face), 318.6 ± 31.6 ms and 477.7 ± 43.6 (hand), and 627.6 ± 84.4 and 774.2 ± 94.0 (foot sole). N2/P2 amplitudes were 10.7 ± 4.1, 11.3 ± 4.1 and 7.5 ± 4.1 µV. During A-fibre block no CEPs were detectable in the grand average, which restored 10 min after block removal. CONCLUSIONS: CEPs were reliably recorded in healthy subjects at the hand, face and foot. Experimentally induced reversible A-delta fibre function loss was detected by CEPs. Functional recovery was assessed as well. This study is basis for further CEP evaluation studies and might be the first step for implementing CEPs in clinical routine for the early diagnosis of small-fibre disease. WHAT DOES THIS STUDY ADD?: Cold-evoked potentials are capable of reliably measuring A-delta fibre integrity, loss of function and functional recovery in healthy subjects, which is an essential prerequisite for diagnostic use in patients with small-fibre disease.

Brainspotting: sustained attention, spinothalamic tracts, thalamocortical processing, and the healing of adaptive orientation truncated by traumatic experience.

We set out hypotheses which are based in the technique of Brainspotting (Grand, 2013) [1] but have wider applicability within the range of psychotherapies for post-traumatic and other disorders. We have previously (Corrigan and Grand, 2013) [2] suggested mechanisms by which a Brainspot may be established during traumatic experience and later identified in therapy. Here we seek to formulate mechanisms for the healing processing which occurs during mindful attention to the Brainspot; and we generate hypotheses about what is happening during the time taken for the organic healing process to flow to completion during the therapy session and beyond it. Full orientation to the aversive memory of a traumatic experience fails to occur when a high level of physiological arousal that is threatening to become overwhelming promotes a neurochemical de-escalation of the activation: there is then no resolution. In Brainspotting, and other trauma psychotherapies, healing can occur when full orientation to the memory is made possible by the superior colliculi-pulvinar, superior colliculi-mediodorsal nucleus, and superior colliculi-intralaminar nuclei pathways being bound together electrophysiologically for coherent thalamocortical processing. The brain's response to the memory is "reset" so that the emotional response experienced in the body, and conveyed through the paleospinothalamic tract to the midbrain and thalamus and on to the basal ganglia and cortex, is no longer disturbing. Completion of the orientation "reset" ensures that the memory is reconsolidated without distress and recollection of the event subsequently is no longer dysphorically activating at a physiological level.

The neurology of itch.

Research over the past 15 years has helped to clarify the anatomy and physiology of itch, the clinical features of neuropathic itch syndromes and the scientific underpinning of effective treatments. Two itch-sensitive pathways exist: a histamine-stimulated pathway that uses mechanically insensitive C-fibres, and a cowhage-stimulated pathway primarily involving polymodal C-fibres. Interactions with pain continue to be central to explaining various aspects of itch. Certain spinal interneurons (Bhlhb5) inhibit itch pathways within the dorsal horn; they may represent mediators between noxious and pruritic pathways, and allow scratch to inhibit itch. In the brain, functional imaging studies reveal diffuse activation maps for itch that overlap, but not identically, with pain maps. Neuropathic itch syndromes are chronic itch states due to dysfunction of peripheral or central nervous system structures. The most recognized are postherpetic itch, brachioradial pruritus, trigeminal trophic syndrome, and ischaemic stroke-related itch. These disorders affect a patient's quality of life to a similar extent as neuropathic pain. Treatment of neuropathic itch focuses on behavioural interventions (e.g., skin protection) followed by stepwise trials of topical agents (e.g., capsaicin), antiepileptic drugs (e.g., gabapentin), injection of other agents (e.g., botulinum A toxin), and neurostimulation techniques (e.g., cutaneous field stimulation). The involved mechanisms of action include desensitization of nerve fibres (in the case of capsaicin) and postsynaptic blockade of calcium channels (for gabapentin). In the future, particular histamine receptors, protease pathway molecules, and vanilloids may serve as targets for novel antipruritic agents.

In vivo microdialysis of glutamate in ventroposterolateral nucleus of thalamus following electrolytic lesion of spinothalamic tract in rats.

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.

The location of the major ascending and descending spinal cord tracts in all spinal cord segments in the mouse: actual and extrapolated.

Information on the location of the major spinal cord tracts in the mouse is sparse. We have collected published data on the position of these tracts in the mouse and have used data from other mammals to identify the most likely position of tracts for which there is no mouse data. We have plotted the position of six descending tracts (corticospinal, rubrospinal, medial and lateral vestibulospinal, rostral and caudal reticulospinal) and eight ascending tracts (gracile; cuneate; postsynaptic dorsal columns; dorsolateral, lateral, and anterior spinothalamic; dorsal and ventral spinocerebellar) on diagrams of transverse sections of all mouse spinal cord segments from the first cervical to the third coccygeal segment.

Do we activate specifically somatosensory thin fibres with the concentric planar electrode? A scalp and intracranial EEG study.

Laser-evoked potentials (LEPs) are acknowledged as the most reliable laboratory tool for assessing thermal and pain pathways. Electrical stimulation with a newly developed planar concentric electrode, delivering stimuli limited to the superficial skin layers, has been suggested to provide selective activation of Aδ fibres without the inconveniences linked to laser stimulation. The aim of our study was to compare the scalp and intracranial responses to planar concentric electrode stimulation (CE-SEPs) with those of LEPs and standard somatosensory-evoked potentials (SEPs). Sixteen healthy subjects, 6 patients with intracortical electrodes, and 2 patients with selective lesions of the spinothalamic pathway were submitted to Neodymium:Yttrium-Aluminium-Perovskite laser stimulations, and electrical stimulations using standard electrodes or planar concentric electrodes (CE). In both healthy controls and epileptic implanted patients, CE- and standard SEPs showed significantly shorter latencies than LEPs. This is consistent with Aß-fibre activation, peripheral activation time being unable to account for longer LEP latencies. In the patients with spinothalamic lesions, LEPs were absent after stimulation of the affected territory, while CE-SEPs were still present. For these 2 reasons, we conclude that the planar CE does not selectively activate the Aδ and C fibers, but coexcites a significant proportion of large myelinated Aß fibres that dominate the ensuing cortical response. The use of CE-SEPs for the detection of spinothalamic system lesions is therefore not warranted; the planar electrode can, however, represent a useful tool to study nociceptive reflexes, which can be reliably elicited even in the presence of Aß coactivation.

A pivotal role of lumbar spinothalamic cells in the regulation of ejaculation via intraspinal connections.

INTRODUCTION: A population of lumbar spinothalamic cells (LSt cells) has been demonstrated to play a pivotal role in ejaculatory behavior and comprise a critical component of the spinal ejaculation generator. LSt cells are hypothesized to regulate ejaculation via their projections to autonomic and motor neurons in the lumbosacral spinal cord. AIM: The current study tested the hypothesis that ejaculatory reflexes are dependent on LSt cells via projections within the lumbosacral spinal cord. METHODS: Male rats received intraspinal injections of neurotoxin saporin conjugated to substance P analog, previously shown to selectively lesion LSt cells. Two weeks later, males were anesthetized and spinal cords were transected. Subsequently, males were subjected to ejaculatory reflex paradigms, including stimulation of the dorsal penile nerve (DPN), urethrogenital stimulation or administration of D3 agonist 7-OH-DPAT. Electromyographic recordings of the bulbocavernosus muscle (BCM) were analyzed for rhythmic bursting characteristic of the expulsion phase of ejaculation. In addition, a fourth commonly used paradigm for ejaculation and erections in unanesthetized, spinal-intact male rats was utilized: the ex copula reflex paradigm. MAIN OUTCOME MEASURES: LSt cell lesions were predicted to prevent rhythmic bursting of BCM following DPN, urethral, or pharmacological stimulation, and emissions in the ex copula paradigm. In contrast, LSt cell lesions were not expected to abolish erectile function as measured in the ex copula paradigm. RESULTS: LSt cell lesions prevented rhythmic contractions of the BCM induced by any of the ejaculatory reflex paradigms in spinalized rats. However, LSt cell lesions did not affect erectile function nor emissions determined in the ex copula reflex paradigm. CONCLUSIONS: These data demonstrate that LSt cells are essential for ejaculatory, but not erectile reflexes, as previously reported for mating animals. Moreover, LSt cells mediate ejaculation via projections within the spinal cord, presumably to autonomic and motor neurons.

Evidence of different spinal pathways for the warmth evoked potentials.

OBJECTIVE: To investigate the presence of multiple spinothalamic pathways for warmth in the human spinal cord. METHODS: Laser evoked potentials to C-fiber stimulation (C-LEPs) were recorded in 15 healthy subjects after warmth stimulation of the dorsal midline at C5, T2, T6, and T10 vertebral levels. This method allowed us to calculate the spinal conduction velocity (CV) in two different ways: (1) the reciprocal of the slope of the regression line was obtained from the latencies of the different C-LEP components, and (2) the distance between C5 and T10 was divided by the latency difference of the responses at the two sites. In particular, we considered the C-N1 potential, generated in the second somatosensory (SII) area, and the late C-P2 response, generated in the anterior cingulate cortex (ACC). RESULTS: The calculated CV of the spinal fibers generating the C-N1 potential (around 2.5m/s) was significantly different (p<0.01) from the one of the pathway producing the P2 response (around 1.4m/s). CONCLUSIONS: Our results suggest that the C-N1 and the C-P2 components are generated by two parallel spinal pathways. SIGNIFICANCE: Warmth sensation is subserved by parallel spinothalamic pathways, one probably reaching the SII area, the other the ACC.

Cortical hyperexcitability in response to preserved spinothalamic inputs immediately after spinal cord hemisection.

Chronic injury of the main somatosensory pathways ascending along the spinal cord - the dorsal columns and the spinothalamic tract - can produce both changes in the organization of cortical somatotopic maps and neuropathic pain. Little is known, however, about the early neurophysiological changes occurring immediately after injury. We bilaterally recorded the neural activity of the hindpaw representation of the primary somatosensory cortex evoked by stimuli delivered to the hindpaws before and immediately after a thoracic spinal cord hemisection in anesthetized rats. This unilateral spinal cord injury allowed us to separately investigate the cortical effects of deafferenting the dorsal column (stimuli ipsilateral to the hemisection) or the spinothalamic tract (stimuli contralateral to the hemisection). The hemisection produced immediate bilateral changes in the cortical responses evoked by stimuli delivered to the hindpaw ipsilateral to the hemisection (deafferented dorsal column): an expected loss of classical short-latency cortical responses, accompanied by an unexpected appearance of long-latency activations. At the population level, these activations reflected a progressive stimulus-induced transition of the hindpaw somatosensory cortex from up-and-down states to a sustained activated state. At the single-cell level, these cortical activations resembled the "wind-up" typically observed - with the same type of stimuli - in the dorsal horn cells originating the spinothalamic tract. Virtually no changes were observed in the responses evoked by stimuli delivered to the hindpaw contralateral to the hemisection (deafferented spinothalamic tract). These results suggest that spinal cord hemisection immediately produces an abnormal hyperexcitability of the primary somatosensory cortex in response to preserved spinothalamic inputs from the hindpaw. This immediate cortical hyperexcitability could be important to understand the long-term development of cortical reorganization and neuropathic pain after incomplete spinal cord lesions.

Comparison of activity characteristics of the cuneate nucleus and thoracic spinal neurons receiving noxious cardiac and/or somatic inputs in rats.

Previous studies have shown that the gracile nucleus in postsynaptic dorsal column pathway plays an important role in conveying nociceptive information from pelvic visceral organs. The purpose of this study was to compare effects of a noxious cardiac stimulus on neuronal activity in the cuneate nucleus and upper thoracic spinal cord in rats. Extracellular potentials of single neurons in the cuneate nucleus and upper thoracic (T3) spinal cord were recorded in pentobarbital anesthetized, ventilated and paralyzed male rats. To activate cardiac nociceptors, a silicone tube was placed in the pericardial sac over the left ventricle to administer a solution of bradykinin (10 microg/ml, 0.2 ml, 1 min). The number of cuneate neurons responding to intrapericardial bradykinin (IB, 15.6%, 17/109) was significantly less than for T3 neurons (43.2%, 48/111, P<0.05). IB excited 9/17 (52.9%) cuneate neurons and inhibited eight neurons. In contrast, IB excited a significantly higher percentage of responding spinal neurons than those in cuneate nucleus (43/48, 89.6%, P<0.01). The ratio of short latency/long-lasting responses of cuneate neurons to IB (14/3) were significant higher than responses of spinal neurons (26/22, P<0.05). Spontaneous activity (5.5+/-0.7 imp/s), response amplitudes (6.0+/-0.6 imp/s) and durations (83.4+/-10.8 sec) of cuneate neurons excited by IB were significantly less than for spinal neurons (11.5+/-1.3 imp/s, 20.4+/-2.0 imp/s and 104.9+/-7.0 imp/s, P<0.01, P<0.01, P<0.05), respectively. These results indicate that the cuneate nucleus neurons play a relatively minor role in transmission of cardiac nociceptive information in comparison to upper thoracic spinal neurons.

Gustatory itching: an unusual complication following superficial parotidectomy.

OBJECTIVE: We report the previously undocumented complication of gustatory itching following superficial parotidectomy. METHOD: Case report and review of the English literature concerning Frey's syndrome, complications of superficial parotidectomy and the pathophysiology of itching. RESULTS: A 49-year-old woman developed gustatory itching following a superficial parotidectomy. Her symptoms were satisfactorily managed with topical and oral antihistamine preparations. We propose a neurophysiological pathway involving acetylcholine and histamine to explain this phenomenon. CONCLUSION: To our knowledge, this is the first documented case of gustatory itching following superficial parotidectomy. The use of antihistamine preparations appears to effectively manage this symptom, without the need for invasive procedures.

A quantitative study of brainstem projections from lamina I neurons in the cervical and lumbar enlargement of the rat.

Lamina I of the rat spinal cord contains neurons that project to various brain areas including thalamus, periaqueductal grey matter (PAG), lateral parabrachial area (LPb), caudal ventrolateral medulla and a region in dorsal medulla that includes the nucleus tractus solitarius and dorsal reticular nucleus. We have shown that spinothalamic lamina I neurons are infrequent in rat lumbar enlargement, where they constitute approximately 5% of the estimated 400 projection neurons on each side of the L4 segment (Al-Khater and Todd, 2009). They are more numerous in cervical enlargement, but the total number of lamina I projection neurons in this region was not known. Here we have used paired injections of retrograde tracers into the brainstem to estimate the number of lamina I projection cells in the C7 segment. Our results suggest that there are approximately 215 lamina I projection cells per side, and that spinothalamic cells therefore make up approximately 42% of this population. The proportion of lamina I projection neurons labelled from PAG is higher in cervical than lumbar enlargement, while the proportion labelled from dorsal medulla is similar in the two regions. We also found that lamina I cells in L4 that project to the dorsal medulla are included in the population retrogradely labelled from LPb, thus confirming the estimate that there are around 400 lamina I projection cells in this segment.

A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states.

Translational control through the mammalian target of rapamycin (mTOR) is critical for synaptic plasticity, cell growth, and axon guidance. Recently, it was also shown that mTOR signaling was essential for the maintenance of the sensitivity of subsets of adult sensory neurons. Here, we show that persistent pain states, but not acute pain behavior, are substantially alleviated by centrally administered rapamycin, an inhibitor of the mTOR pathway. We demonstrate that rapamycin modulates nociception by acting on subsets of primary afferents and superficial dorsal horn neurons to reduce both primary afferent sensitivity and central plasticity. We found that the active form of mTOR is present in a subpopulation of myelinated dorsal root axons, but rarely in unmyelinated C-fibers, and heavily expressed in the dorsal horn by lamina I/III projection neurons that are known to mediate the induction and maintenance of pain states. Intrathecal injections of rapamycin inhibited the activation of downstream targets of mTOR in dorsal horn and dorsal roots and reduced the thermal sensitivity of A-fibers. Moreover, in vitro studies showed that rapamycin increased the electrical activation threshold of Adelta-fibers in dorsal roots. Together, our results imply that central rapamycin reduces neuropathic pain by acting both on an mTOR-positive subset of A-nociceptors and lamina I projection neurons and suggest a new pharmacological route for therapeutic intervention in persistent pain states.

The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys.

Classically, the spinothalamic (ST) system has been viewed as the major pathway for transmitting nociceptive and thermoceptive information to the cerebral cortex. There is a long-standing controversy about the cortical targets of this system. We used anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 in the Cebus monkey to label the cortical areas that receive ST input. We found that the ST system reaches multiple cortical areas located in the contralateral hemisphere. The major targets are granular insular cortex, secondary somatosensory cortex and several cortical areas in the cingulate sulcus. It is noteworthy that comparable cortical regions in humans consistently display activation when subjects are acutely exposed to painful stimuli. We next combined anterograde transneuronal transport of virus with injections of a conventional tracer into the ventral premotor area (PMv). We used the PMv injection to identify the cingulate motor areas on the medial wall of the hemisphere. This combined approach demonstrated that each of the cingulate motor areas receives ST input. Our meta-analysis of imaging studies indicates that the human equivalents of the three cingulate motor areas also correspond to sites of pain-related activation. The cingulate motor areas in the monkey project directly to the primary motor cortex and to the spinal cord. Thus, the substrate exists for the ST system to have an important influence on the cortical control of movement.

Cellular basis of itch sensation.

Itch and pain are two distinct sensations. Although our previous study suggested that gastrin-releasing peptide receptor (GRPR) is an itch-specific gene in the spinal cord, a long-standing question of whether there are separate neuronal pathways for itch and pain remains unsettled. We selectively ablated lamina I neurons expressing GRPR in the spinal cord of mice. These mice showed profound scratching deficits in response to all of the itching (pruritogenic) stimuli tested, irrespective of their histamine dependence. In contrast, pain behaviors were unaffected. Our data also suggest that GRPR+ neurons are different from the spinothalamic tract neurons that have been the focus of the debate. Together, the present study suggests that GRPR+ neurons constitute a long-sought labeled line for itch sensation in the spinal cord.