Date

6-1-2012

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

The brainstem regulates core functions of the body, both at rest and in response to threat. The mechanism of this regulation is still under study, although core regulatory areas have been identified. The rostral ventromedial medulla (RVM) is a brainstem region that has been extensively studied in the context of somatosensory responsiveness and pain. Under different behavioral settings, neurons in the RVM can facilitate or inhibit the detection of tissue damage (nociception). The nociceptive modulation from the RVM is governed by two populations of neurons, the ON-cells and the OFF-cells. Firing of ON-cells increases sensitivity to stimuli and facilitates spinal reflexes, whereas OFF-cell activity decreases sensitivity and produces analgesia. The responses of ON- and OFF-cells to acute injury have been well studied, but the role of these RVM neurons in other behavioral contexts is less well understood. The first aim of this thesis is to contrast the contributions of ON- and OFF-cells during acute injury versus chronic pain. The second aim is to examine other modulatory roles of RVM neurons and how core regulatory functions overlap with pain modulation in the RVM. The RVM plays an important role in chronic pain, although the underlying neuronal contributions remain unclear. In acute pain, increased ON-cell activity drives hyperalgesia, and from that observation it has been hypothesized that ON-cells also maintain chronic pain. In a model of chronic inflammatory pain, an initial subcutaneous injection of an irritant into the hindpaw produced immediate increased responsiveness to stimulation (hyperalgesia). This acute hyperalgesia was blocked by inhibiting the ON-cells. Animals with irritant injections that were allowed to recover continued to display hyperalgesia in the days after the injection, and ON- and OFF-cells similarly showed increased sensitivity to stimulation. However, in a model of chronic inflammation, inhibition of ON-cells did not reverse the hyperalgesia, but actually exacerbated it. Thus ON-cells drive hyperalgesia in acute but not chronic injury. This finding reinforces the idea that chronic pain is not simply an extension of an acute injury. As ON- and OFF-cells can separately modulate acute and chronic pain, and their activity may also separately modulate other core regulatory functions associated with the RVM, such as respiration and heart rate. To examine how RVM neuronal activity intersected with respiration, I built a device for monitoring respiration during RVM manipulations. From this device, we find that RVM neurons concurrently modulate respiration and analgesia, such that opioid injection locally in the RVM depresses respiration and produces analgesia. However, these modulatory functions are separable, such that analgesia is possible without respiratory depression. Manipulations of ON-cell activity modulate respiration, whereas changes in OFF-cell activity were only associated with analgesia. The separate roles of ON- and OFF-cells in modulating pain and respiration open the possibility of developing potent, opioid-like painkillers that do not depress respiration. Collectively, these results show a separation of function between ON- and OFF-cells. ON-cells modulation core functions related to acute injury or threat, including somatosensory, respiratory, and cardiovascular responsiveness. Conversely, OFF-cell activity was specifically related to the inhibition of pain, such that decreased OFF-cell activity can be a mechanism of pain facilitation. A greater understanding of RVM physiology will aid in improved treatment of chronic pain states and the development of analgesic drugs with fewer side effects.

Identifier

doi:10.6083/M48G8HPB

Division

Neuroscience Graduate Program

School

School of Medicine

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