Itch is an everyday sensation, but when associated with disease or infection it can be chronic and debilitating. Several forms of itch can be blocked using antihistamines, but others cannot and these constitute an important clinical problem. Little information is available on the mechanisms underlying itch that is produced by nonhistaminergic mechanisms. We examined the responses of spinothalamic tract neurons to histaminergic and, for the first time, nonhistaminergic forms of itch stimuli. Fifty-seven primate spinothalamic tract (STT) neurons were identified using antidromic activation techniques and examined for their responses to histamine and cowhage, the nonhistaminergic itch-producing spicules covering the pod of the legume Mucuna pruriens. Each examined neuron had a receptive field on the hairy skin of the hindlimb and responded to noxious mechanical stimulation. STT neurons were tested with both pruritogens applied in a random order and we found 12 that responded to histamine and seven to cowhage. Each pruritogen-responsive STT neuron was activated by the chemical algogen capsaicin and two-thirds responded to noxious heat stimuli, demonstrating that these neurons convey chemical, thermal, and mechanical nociceptive information as well. Histamine or cowhage responsive STT neurons were found in both the marginal zone and the deep dorsal horn and were classified as high threshold and wide dynamic range. Unexpectedly, histamine and cowhage never activated the same cell. Our results demonstrate that the spinothalamic tract contains mutually exclusive populations of neurons responsive to histamine or the nonhistaminergic itch-producing agent cowhage.

Multiple neural pathways and molecular mechanisms responsible for producing the sensation of itch have recently been identified, including histamine-independent pathways. Physiological, molecular, behavioral and brain imaging studies are converging to describe these pathways and their close association with pain processing. Some conflicting results have arisen, and the precise relationship between itch and pain remains controversial. A better understanding of the generation of itch and of the intrinsic mechanisms that inhibit itch after scratching should facilitate the search for new methods to alleviate clinical pruritus (itch). In this review, we describe the current understanding of the production and inhibition of itch. A model of itch processing within the central nervous system (CNS) is proposed.

Fibers projecting from several levels of the spinal cord to the diencephalon and telencephalon were labeled anterogradely with Phaseolus vulgaris leucoagglutinin injected iontophoretically. Labeled fibers in the thalamus confirmed projections previously observed. In addition, many labeled fibers were seen in the hypothalamus and in telencephalic areas not generally recognized previously as receiving such projections. In the hypothalamus, these areas included the lateral hypothalamus (including the medial forebrain bundle), the posterior hypothalamic area, the dorsal hypothalamic area, the dorsomedial nucleus, the paraventricular nucleus, the periventricular area, the suprachiasmatic nucleus, and the lateral and medial preoptic areas. In the telencephalon, areas with labeled fibers included the ventral pallidum, the globus pallidus, the substantia innominata, the basal nucleus of Meynert, the amygdala (central nucleus), the horizontal and vertical limbs of the diagonal band of Broca, the medial and lateral septal nuclei, the bed nucleus of the stria terminalis, the nucleus accumbens, infralimbic cortex, and medial orbital cortex. These results suggest that somatosensory, possibly including visceral sensory, information is carried directly from the spinal cord to areas in the brain involved in autonomic regulation, motivation, emotion, attention, arousal, learning, memory, and sensory-motor integration. Many of these areas are associated with the limbic system.

SUMMARY Glutamine tract expansion triggers nine neurodegenerative diseases by conferring toxic properties to the mutant protein. In SCA1, phosphorylation of ATXN1 at Ser776 is thought to be key for pathogenesis. Here we show that replacing Ser776 with a phospho-mimicking Asp converted ATXN1 with a wild type glutamine tract into a pathogenic protein. ATXN1[30Q]-D776-induced disease in Purkinje cells shared most features with disease caused by ATXN1[82Q] having an expanded polyglutamine tract. However, in contrast to disease induced by ATXN1[82Q] that progresses to cell death, ATXN1[30Q]-D776 failed to induce cell death. These results support a model where pathogenesis involves changes in regions of the protein in addition to the polyglutamine tract. In ATXN1, placing an Asp at residue 776 mimics this change. Moreover, disease initiation and progression to neuronal dysfunction are distinct from induction of cell death. Ser776 is critical for the pathway to neuronal dysfunction, while an expanded polyglutamine tract is essential for neuronal death.

Itch is relieved by scratching, but the neural mechanisms that are responsible for this are unknown. Spinothalamic tract (STT) neurons respond to itch-producing agents and transmit pruritic information to the brain. We observed that scratching the cutaneous receptive field of primate STT neurons produced inhibition during histamine-evoked activity but not during spontaneous activity or activity evoked by a painful stimulus, suggesting that scratching inhibits the transmission of itch in the spinal cord in a state-dependent manner.Itch is an unpleasant sensation that is associated with the desire to scratch. For most itches, relief is obtained by scratching in or around the region of itchy skin. However, itch that is coincident with skin disease or systemic disorders can be severe. In these circumstances, the desire to scratch is often overwhelming, but incessant scratching is harmful and leads to itch-scratch cycles that damage the skin and exacerbate the problem 1 . The mechanism by which scratching sup-presses itch is unknown. However, it has been hypothesized that this mechanism occurs in the CNS because noxious counterstimuli (for example, scratching) reduce itch when delivered many centimeters away from the site of itching and itch does not develop in a zone of cutaneous centrally mediated allodynia 2-5. Histamine-sensitive dorsal horn neurons with unidentified projections are variably depressed by counterstimuli in rats6; however, unlike monkeys7, rats do not scratch in response to histamine, complicating the interpretation of these data with regard to itch.In humans, anterolateral cordotomy eliminates the perception of itch from contralateral body sites below the lesion, implicating the STT in the transmission of pruritic information to the brain 8 . STT neurons can be activated for many minutes following the cutaneous application of itch-producing agents such as histamine 9-11 , matching the sensation of itch in humans 12 . Therefore, we examined whether the responses to histamine in primate STT neurons could be inhibited by scratching in the receptive field. STT neurons were recorded in the lumbar dorsal horn and were identified by antidromic stimulation (Supplementary Methods and Supplementary Fig. 1 Every neuron tested had a mechanically sensitive receptive field and was excited by scratching (n = 28). Repeated scratches to the receptive field of single STT neurons reliably evoked similar discharges (Fig. 1). Two-thirds of STT neurons showed an after-discharge following scratching (Fig. 1b).Histamine (20 μg in 10 μL) was then injected intradermally into the receptive field. In eight neurons that responded to histamine ( Supplementary Fig. 2 online), the receptive field was scratched for 10 s during the response. Each histamine-responsive neuron showed fewer action potentials during the 10-s period immediately following the scratch than during the 10-s period before the scratch (Fig. 2). Most neurons increased their discharge during scratching, but two cells appeared to reduce their discharge ...