No abstract

The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation, and exerts anti-nociceptive and pro-nociceptive influences mediated by two distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a “burst” of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide (CGRP), suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of “bottom-up” nociceptive drive to RVM pain-modulating neurons is relayed through the parabrachial complex. While the parabrachial complex is well-known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.

Nerve injury can lead to mechanical hypersensitivity in both humans and animal models, such that innocuous touch produces pain. Recent functional studies have demonstrated a critical role for descending pain-facilitating influences from the rostral ventromedial medulla (RVM) in neuropathic pain, but the underlying mechanisms and properties of the relevant neurons within the RVM are essentially unknown. We therefore characterized mechanical responsiveness of physiologically characterized neurons in the RVM after spinal nerve ligation, a model of neuropathic pain that produces robust mechanical hyperalgesia and allodynia. RVM neurons were studied 7-14 d after spinal nerve ligation, and classified as "on-cells," "off-cells," or "neutral cells" using standard criteria of changes in firing associated with heat-evoked reflexes. On-cells are known to promote nociception, and off-cells to suppress nociception, whereas the role of neutral cells in pain modulation remains an open question. Neuronal and behavioral responses to innocuous and noxious mechanical stimulation were tested using calibrated von Frey filaments (4 -100 g) applied to the hindpaws ipsilateral and contralateral to the injury, and in sham-operated and unoperated control animals. On-and off-cells recorded in nerve-injured animals exhibited novel responses to innocuous mechanical stimulation, and enhanced responses to noxious mechanical stimulation. Neuronal hypersensitivity in the RVM was correlated with behavioral hypersensitivity. Neutral cells remained unresponsive to cutaneous stimulation after nerve injury. These data demonstrate that both on-and off-cells in the RVM are sensitized to innocuous and noxious mechanical stimuli after nerve injury. This sensitization likely contributes to allodynia and hyperalgesia of neuropathic pain states.

No abstract

Two broad hypotheses have been advanced to explain the clinical efficacy of deep brain stimulation (DBS) in the subthalamic nucleus (STN) for treatment of Parkinson's disease. One is that stimulation inactivates STN neurons, producing a functional lesion. The other is that electrical stimulation activates the STN output, thus "jamming" pathological activity in basal ganglia-corticothalamic circuits. Evidence consistent with both concepts has been adduced from modeling and animal studies, as well as from recordings in patients. However, the stimulation parameters used in many recording studies have not been well matched to those used clinically. In this study, we recorded STN activity in patients with Parkinson's disease during stimulation delivered through a clinical DBS electrode using standard therapeutic stimulus parameters. A microelectrode was used to record the firing of a single STN neuron during DBS (3-5 V, 80-200 Hz, 90- to 200-micros pulses; 33 neurons/11 patients). Firing rate was unchanged during the stimulus trains, and the recorded neurons did not show prolonged (s) changes in firing rate on termination of the stimulation. However, a brief (approximately 1 ms), short-latency (6 ms) postpulse inhibition was seen in 10 of 14 neurons analyzed. A subset of neurons displayed altered firing patterns, with a predominant shift toward random firing. These data do not support the idea that DBS inactivates the STN and are instead more consistent with the hypothesis that this stimulation provides a null signal to basal ganglia-corticothalamic circuitry that has been altered as part of Parkinson's disease.