Research

Dr. LaMotte's laboratory investigates the peripheral and central neural mechanisms of pain, itch and touch.

The neural basis of itch is poorly understood despite its clinical importance. We are currently addressing the problem by means of a NIH funded Program Project entitled "Neural Mechanisms of Itch" (Robert LaMotte, Principal Investigator).The goal is to identify neurons mediating itch and itchy skin and to characterize the neurons that modulate pruritic sensations and sensory states. These modulatory neurons might then be targeted in clinical treatments of chronic pruritus.

The purpose of the project is to investigate the peripheral and central coding mechanisms of itch and the modification of itch by nociceptive and other types of cutaneous stimulation. The approach is to correlate psychophysical measurements of itch in humans (Project 1) with electrophysiological recordings from pruriceptive and nociceptive peripheral nerve fibers in the monkey (Project 2.) and pruriceptive and nociceptive spinothalamic tract neurons in the monkey (Project 3) using the same types of pruritic and nociceptive stimuli. The correlations are used to identify candidate neural mechanisms that code the sensation of itch and itchy skin and the neural mechanisms that modulate itch and itchy skin.

Project 1 (Robert. LaMotte, PI, Barry Green, Co-investigator) is conducted at Yale University School of Medicine., Project 2 at Johns Hopkins School of Medicine (Matthias Ringkamp, PI, Richard. Meyer, Co-investigator.) and Project 3 at University of Minnesota School of Medicine. (Glen Giesler, PI, Donald Simone, Co-investigator). By increasing our understanding of the peripheral and central neural mechanisms that code and modulate itch, our combined studies may provide new targets for novel therapies to relieve itch.

We are using a model of chronic compression of the dorsal root ganglion (CCD) that might occur, for example, with a laterally herniated disk or foraminal stenosis. This type of pain might be produced in humans, for example, after injuries and degenerative disorders of the spine. CCD is produced in the rat by the insertion a rod into the intervertebral foramen, one at L4 and another at L5. It is accompanied by cutaneous hyperalgesia in the ipsilateral hind paw and spontaneous ectopic discharges (SE) that originate in the dorsal root ganglion (DRG) in neurons with intact, conducting axons. An increased excitability of subpopulations of DRG cell bodies of different sizes after CCD, evidenced by SE, and/or lowered current and voltage threshold, is exhibited not only in the intact ganglion but also in dissociated DRG neurons in short term culture. Our recent studies of the ionic mechanisms of CCD-induced neuronal hyperexcitability in (medium-sized) DRG cells reveal changes including an increase in the hyperpolarization cation current (Ih), a decrease in fast inactivating, transient potassium current, a negative shift in the activation curve of TTX-S channels and an increase in peak TTX-resistant sodium current.

Other effects we have found to occur after CCD include an upregulation in the expression of the chemokine receptor (CCR2) and its preferred ligand, MCP-1. Many CCD, but not control, DRG neurons developed an excitatory response to MCP-1. Thus, MCP-1/CCR2 signaling is directly involved with a chronic compression injury and may contribute to CCD induced neuronal hyperexcitability and neuropathic pain.

Texture

We used methods of photolithography to construct novel surface microtextures. We investigated the smallest bump that could be felt with the finger pad and the types of mechanoreceptors that could account for this capacity. In a subsequent study we investigated which populations of mechanoreceptors are likely to respond to finely embossed surfaces and which provide information about the relative motion and direction of a smooth surface moved across the skin.

The tactual properties of objects are typically perceived by manual palpation. But correlative electrophysiological studies of tactile sensory neurons require that the same stimulus attribute be repetitively delivered under the same stimulus conditions. Thus, corollary aims were to produce stimulus objects expressing graded properties of an attribute such as curvature or compliance and to develop methods of delivering these objects to the passive hand in a way that elicited the cutaneous mechanical events occurring during active touch.

Shape

The shape of an object can be defined as the distribution of curvatures at any given point on its surface. We investigated the sensory coding of object curvature in responses of cutaneous mechanoreceptive nerve fibers supplying the primate fingerpad. The slowly adapting Type I mechanoreceptive fibers were exquisitely sensitive to differences in the amount and rate of change in the curvature of the skin brought about by stroking or stepping objects of differing curvature across the fingerpad. These objects included step shapes, cylindrical bars, spheres, toroids and wavy surfaces consisting of alternating curvature. The shape, orientation and trajectory of an object was found to be encoded most accurately in the spatially distributed pattern of peripheral neural discharge rates in the slowly-adapting (as opposed to rapidly-adapting) mechanoreceptor population.

Softness

Softness specimens consisting of silicon rubber disks of differing compliance were passively applied to the skin or actively palpated with the fingerpad or by means of a tool held in contact with the skin. A major goal was to determine what kinds of sensory cues are used to discriminate differences in the softness of objects.

Servo-controlled Cutaneous Stimulators

Our tactile stimulators were designed to move an object over the skin in a manner that mimicked the mechanical events occurring when the object is stoked with the fingerpad. The first prototype was hydraulically controlled and used in our first studies of texture and shape (1980- 1990. Then, we used a commercially available 3-axis translation table (brushless, linear motors, Anorad Corp).. A stepping motor mounted on the vertical (Z-) axis was used to rotate one of a number of objects on plate into position before lowering the object onto the skin (see video). However, because the servo-control of force was relatively slow, considering the large mass of the system, we finally settled on a design where a single, small object (a toroid or spheroid) was mounted to a lever arm attached that was attached to the shaft of a high-speed torque (Aurora Scientific). The torque motor was mounted to the rotary plate. Rotation of the plate allowed us to change the orientation of the toroidally shaped object (LaMotte et al.1998) shape before bringing the object onto the skin. The torque motor was then used to maintain the compressional force of the object against the skin as the object was translated along a linear trajectory over the fingerpad.