Summary The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain 1 – 4 . Projection neurons (PNs) of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery channel through these spinal PNs en route to the brain. However, the organizational logic of the anterolateral pathway remains elusive. Here, we show that two PN populations that express structurally related GPCRs, TACR1 and GPR83, form parallel ascending circuit modules that cooperate to convey tactile, thermal and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons (PBN L ). Axons of Tacr1 - and Gpr83 -expressing spinoparabrachial (SPB) neurons innervate distinct sets of PBN L subnuclei, and strong optogenetic stimulation of their axon terminals induces distinct escape behaviors and autonomic responses. Moreover, Gpr83 -expressing SPB neurons are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Remarkably, the valence associated with activation of Gpr83 -expressing SPB neurons is either positive or negative depending on stimulus intensity. These findings reveal anatomically, physiologically, and functionally distinct SPB tract subdivisions that underlie affective aspects of touch and pain.
SUMMARY Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation, nociceptor sensitization by inflammatory mediators, and pain and itch behaviors. These experiments provide a rationale for the therapeutic use of peripherally restricted KOR agonists.
The somatosensory input that gives rise to the perceptions of pain, itch, cold and heat are initially integrated in the superficial dorsal horn of the spinal cord. Here, we describe a new approach to investigate these neural circuits in mouse. This semi-intact somatosensory preparation enables recording from spinal output neurons, while precisely controlling somatosensory input, and simultaneously manipulating specific populations of spinal interneurons. Our findings suggest that spinal interneurons show distinct temporal and spatial tuning properties. We also show that modality selectivity — mechanical, heat and cold — can be assessed in both retrogradely labeled spinoparabrachial projection neurons and genetically labeled spinal interneurons. Finally, we demonstrate that interneuron connectivity can be determined via optogenetic activation of specific interneuron subtypes. This new approach may facilitate key conceptual advances in our understanding of the spinal somatosensory circuits in health and disease.DOI: http://dx.doi.org/10.7554/eLife.22866.001
Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is believed to underlie temporal summation of nociceptive input. However, whether spinoparabrachial neurons, which likely contribute to the affective component of pain, undergo wind-up was unknown. Here, we addressed this question and investigated the underlying neural circuit. We show that one-fifth of lamina I spinoparabrachial neurons undergo wind-up, and provide evidence that wind-up in these cells is mediated in part by a network of spinal excitatory interneurons that show reverberating activity. These findings provide insight into a polysynaptic circuit of sensory augmentation that may contribute to the wind-up of pain's unpleasantness.
Itch is a common complaint among patients with cutaneous diseases. H 1 histamine receptor antagonists are the drugs of choice for the treatment of itch, but their effect in ameliorating many pruritic diseases including atopic dermatitis is often unsatisfactory. The reason for this may be due in part to the presence of many itch mediators other than histamine (1), and therefore specific antagonists and inhibitors may not effectively relieve many kinds of pruritic diseases. Although at least two subpopulations of primary afferents (histamine sensitive and insensitive) are involved in itch signaling (2), the types of neurotransmitters involved in itch signaling in the dorsal horn may be far fewer than those of itch mediators in the skin. It was recently reported that gastrin-releasing peptide plays an important role in itch signaling from sensory neurons to the interneurons in the dorsal horn (3). Ablation of dorsal horn neurons expressing gastrin-releasing peptide receptor has been shown to result in the suppression of itch-related responses to histamine and several other itch mediators (3). This raises the possibility that administration of antipruritic agents that act on the dorsal horn will be effective for the treatment of itch of many pruritic diseases.We have recently found that clonidine suppresses the itch-related response of mice to an intradermal injection of serotonin through its action on the α 2 -adrenoceptors in the spinal cord (4). In mice, cyproheptadine, a serotonin and histamine antagonist, inhibits the itch-related response to serotonin, but does not inhibit the response to mosquito allergy (5, 6). Acute topical application of tacrolimus inhibits itch-related responses to mosquito allergy and proteinase-activated receptor-2 (PAR 2 ) agonist, but does not inhibit the responses to serotonin and histamine (7). Itch signals induced by mosquito allergy may be mediated by primary afferents expressing PAR 2 receptors (8). These findings taken together suggest that itch signals of mosquito allergy and serotonin are mediated by separate primary afferents. Therefore, in order to determine whether the stimulation of α 2 -adrenoceptor in the spinal cord would suppress itch induced by different causes, we investigated whether intrathecal clonidine would suppress the itch-related response to mosquito allergy. The descending noradrenergic system exerts tonic inhibition on pain transmission in the dorsal horn mediated by α-adrenoceptors (9, 10). Thus, we also investigated whether the descending monoaminergic systems exert a tonic inhibition on the transmission of itch signals in the spinal cord.Male ICR mice (6 -12-weeks-old; Japan SLC, Shizuoka) were used. They were kept in a room under controlled temperature (22 ± 1°C), humidity (55 ± 10%), and light (light on 7:00 -19:00 h). Food and water were Toyama 930-0194, Japan Received November 29, 2010; Accepted December 30, 2010 Abstract. We investigated whether the descending noradrenergic system regulates allergic itch. Mosquito allergy of the hind paw elici...
This study was conducted to identify the characteristic pharmacological features of GT-0198 that is phenoxymethylbenzamide derivatives. GT-0198 inhibited the function of glycine transporter 2 (GlyT2) in human GlyT2-expressing HEK293 cells and did not bind various major transporters or receptors of neurotransmitters in a competitive manner. Thus, GT-0198 is considered to be a comparatively selective GlyT2 inhibitor. Intravenous, oral, and intrathecal injections of GT-0198 decreased the pain-related response in a model of neuropathic pain with partial sciatic nerve ligation. This result suggests that GT-0198 has an analgesic effect. The analgesic effect of GT-0198 was abolished by the intrathecal injection of strychnine, a glycine receptor antagonist. Therefore, GT-0198 is considered to exhibit its analgesic effect via the activation of a glycine receptor by glycine following presynaptic GlyT2 inhibition in the spinal cord. In summary, GT-0198 is a structurally novel GlyT2 inhibitor bearing a phenoxymethylbenzamide moiety with in vivo efficacy in behavioral models of neuropathic pain.
This study was conducted to identify the mechanosensitive dorsal horn neurons involved in allergic itch. We examined 98 units responsive to cutaneous allergy; 90 showed only immediate responses, which subsided before the onset of itch-related behavior and eight showed immediate and sustained responses, the latter of which was similar in duration to itch-related behavior, suggesting the involvement of sustained units in itch signaling. Sustained units were localized in the superficial, but not deep, layers of the dorsal horn. They were wide dynamic range or nociceptive specific, but not low threshold and four of eight were noxious heat sensitive. The results suggest that a small minority of neurons in the superficial dorsal horn are involved in allergic itch signals.
Abstract. This study was conducted to make a new mouse model of neuropathic pain due to injury to a branch of the sciatic nerve. One of three branches (sural, tibial, and common peroneal nerves) of the sciatic nerve was tightly ligated, and mechanical and cool stimuli were applied to the medial part (tibial and common peroneal nerve territories) of the plantar skin. The three types of nerve injuries produced behavioral mechanical hypersensitivities, and the extent of the hypersensitivities after sural and tibial nerve ligation was larger than that of common peroneal nerve ligation. Sural nerve ligation did not affect motor function of the affected hind paw, but tibial and common peroneal nerve ligation produced motor dysfunction. These results suggest that the ligation of the sural nerve is the most suitable for behavioral study. Sural nerve ligation induced behavioral hypersensitivities to mechanical and cool stimuli, which were almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation increased spontaneous activity and responses of the wide-dynamic range neurons in the lumbar dorsal horn, which were also almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation provides a new mouse model of neuropathic pain, which is easy to prepare and sensitive to gabapentin.
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