Glenn J. Giesler

The Itch-Producing Agents Histamine and Cowhage Activate Separate Populations of Primate Spinothalamic Tract Neurons

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.

The multiple pathways for itch and their interactions with pain

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 on a description of 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 CNS is proposed.

Direct spinal pathways to the limbic system for nociceptive information

The hypothalamus is believed to play important roles in several aspects of nociception. Previously, nociceptive information was thought to reach hypothalamic neurons through indirect, multisynaptic pathways. However, we have found that thousands of neurons throughout the length of the spinal cord in rats send axons directly into the hypothalamus, and many of these axons carry nociceptive information. The axons often follow a complex course, ascending through the contralateral spinal cord, brainstem, thalamus and hypothalamus. They then cross the midline and enter the ipsilateral hypothalamus, turn posteriorly, and continue into the ipsilateral thalamus. These axons might provide nociceptive information to a variety of nuclei in the thalamus and hypothalamus bilaterally.

Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons

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.

Projections from the marginal zone and deep dorsal horn to the ventrobasal nuclei of the primate thalamus

&NA; It has been concluded recently that if a projection from the marginal zone to the ventral posterior lateral (VPL) nucleus exists, it is sparse. Given the importance of the marginal zone in nociception, this conclusion has raised doubts about the significance of the role of the ventrobasal complex in nociception. We have reexamined this projection using injections of the retrograde tracer, cholera toxin subunit B, into one side of the lateral thalamus in macaque monkeys. The injections were confined to the ventrobasal complex (with minimal spread to adjacent nuclei that do not receive spinal projections) in two animals. Many retrogradely labeled neurons were found in lamina I (as well as in lamina V) of the contralateral spinal and medullary dorsal horn. The results are consistent with the view that neurons in the marginal zone contribute prominently to the spinothalamic and trigeminothalamic projections to the VPL and ventral posterior medial (VPM) nuclei. This pathway is likely to be important for the sensory‐discriminative processing of nociceptive information with respect to the location and intensity of painful stimuli.

SCA1-like Disease in Mice Expressing Wild-Type Ataxin-1 with a Serine to Aspartic Acid Replacement at Residue 776

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 phosphomimicking 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. 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.

Afferent input to nucleus submedius in rats: retrograde labeling of neurons in the spinal cord and caudal medulla

In cats, spinal and medullary input to the thalamic nucleus submedius (Sm) arises almost exclusively from neurons in the marginal zone. As a result, it has been proposed that Sm may be specifically involved in nociception. In the present study, we determined the locations of neurons in the spinal cord and caudal medulla that project to Sm in rats. Iontophoretic injections of Fluoro-Gold or pressure injections of Fast blue were made into Sm. In each of the 6 rats that received small injections of Fluoro-Gold into Sm, only a small number (mean = 90) of retrogradely labeled neurons were found throughout the 18 segments of the spinal cord examined. Surprisingly, almost no labeled neurons (less than 1%) were counted in the marginal zone of the spinal cord. The majority were located in the deep dorsal horn and intermediate zone/ventral horn. In contrast, many neurons were labeled in the marginal zone of nucleus caudalis. Injections of Fluoro-Gold into any of a number of nuclei near Sm also labeled only a small number of neurons in the spinal cord and almost no neurons in the marginal zone. Using identical injection parameters, we injected Fluoro-Gold into the ventrobasal complex or posterior thalamic group. Hundreds of neurons in the spinal cord, including many in the marginal zone, were labeled following these injections. These results indicate that the techniques used to inject Fluoro-Gold into Sm were capable of labeling many projection neurons, including those in the marginal zone. Larger pressure injections of Fast blue were also made into Sm of 3 rats. The distribution of labeled neurons in nucleus caudalis and the spinal cord was similar to that following iontophoretic injections of Fluoro-Gold. Again, few marginal zone neurons were labeled in the spinal cord in any of these rats. Therefore, our results indicate that few spinothalamic tract neurons appear to project to Sm or any of several adjacent nuclei, and virtually no marginal zone neurons in the spinal cord project to these areas.

Retrograde labeling of neurons in spinal cord that project directly to nucleus accumbens or the septal nuclei in the rat

Somatosensory information has been thought to ascend from the spinal cord to limbic areas of the telencephalon through indirect, multisynaptic pathways. We now report that injections of Fluoro-gold into either the nucleus accumbens or the septal nuclei labeled hundreds of neurons in the spinal cord. These and our recent anterograde tracing experiments indicate that some spinal cord neurons project directly to the telencephalon and suggest that nucleus accumbens and septal nuclei process somatosensory information.

Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate

Itch of peripheral origin requires information transfer from the spinal cord to the brain for perception. Here, primate spinothalamic tract (STT) neurons from lumbar spinal cord were functionally characterized by in vivo electrophysiology to determine the role of these cells in the transmission of pruriceptive information. One hundred eleven STT neurons were identified by antidromic stimulation and then recorded while histamine and cowhage (a nonhistaminergic pruritogen) were sequentially applied to the cutaneous receptive field of each cell. Twenty percent of STT neurons responded to histamine, 13% responded to cowhage, and 2% responded to both. All pruriceptive STT neurons were mechanically sensitive and additionally responded to heat, intradermal capsaicin, or both. STT neurons located in the superficial dorsal horn responded with greater discharge and longer duration to pruritogens than STT neurons located in the deep dorsal horn. Pruriceptive STT neurons discharged in a bursting pattern in response to the activating pruritogen and to capsaicin. Microantidromic mapping was used to determine the zone of termination for pruriceptive STT axons within the thalamus. Axons from histamine-responsive and cowhage-responsive STT neurons terminated in several thalamic nuclei including the ventral posterior lateral, ventral posterior inferior, and posterior nuclei. Axons from cowhage-responsive neurons were additionally found to terminate in the suprageniculate and medial geniculate nuclei. Histamine-responsive STT neurons were sensitized to gentle stroking of the receptive field after the response to histamine, suggesting a spinal mechanism for alloknesis. The results show that pruriceptive information is encoded by polymodal STT neurons in histaminergic or nonhistaminergic pathways and transmitted to the ventrobasal complex and posterior thalamus in primates.

R7BP Complexes With RGS9-2 and RGS7 in the Striatum Differentially Control Motor Learning and Locomotor Responses to Cocaine

In the striatum, signaling through G protein-coupled dopamine receptors mediates motor and reward behavior, and underlies the effects of addictive drugs. The extent of receptor responses is determined by RGS9-2/Gβ5 complexes, a striatally enriched regulator that limits the lifetime of activated G proteins. Recent studies suggest that the function of RGS9-2/Gβ5 is controlled by the association with an additional subunit, R7BP, making elucidation of its contribution to striatal signaling essential for understanding molecular mechanisms of behaviors mediated by the striatum. In this study, we report that elimination of R7BP in mice results in motor coordination deficits and greater locomotor response to morphine administration, consistent with the essential role of R7BP in maintaining RGS9-2 expression in the striatum. However, in contrast to previously reported observations with RGS9-2 knockouts, mice lacking R7BP do not show higher sensitivity to locomotor-stimulating effects of cocaine. Using a striatum-specific knockdown approach, we show that the sensitivity of motor stimulation to cocaine is instead dependent on RGS7, whose complex formation with R7BP is dictated by RGS9-2 expression. These results indicate that dopamine signaling in the striatum is controlled by concerted interplay between two RGS proteins, RGS7 and RGS9-2, which are balanced by a common subunit, R7BP.