• Neuronal Mechanisms of Chronic Pain Induced by Spinal Cord Injury

      Whitt, Jessica Lucas; Keller, Asaf; Masri, Radi, 1975- (2012)
      Chronic pain develops in most patients who suffer from spinal cord injury (SCI), and manifests as exaggerated responses to painful stimuli (hyperalgesia), pain in response to normally non-painful stimuli (allodynia), and, most commonly, constant spontaneous pain. The mechanisms of SCI-pain have been difficult to identify, though it is hypothesized to develop as a result of thalamic disinhibition. Here we use an electrolytic lesion in the spinal thalamic tract of rats to model SCI-pain. We employ novel behavioral metrics to show that after spinal lesion rats develop both hyperalgesia and spontaneous pain. We tested the hypothesis that these behavioral abnormalities result from reduced inhibition from the zona incerta (ZI) to thalamic nuclei involved in the sensory aspects of pain (the posterior nucleus, PO) and the affective aspects of pain (mediodorsal nucleus, MD). With single unit, extracellular electrophysiological recordings we demonstrate that SCI- pain results from decreased activity in the inhibitory nucleus ZI, which leads to a dramatic increase in spontaneous and evoked neuronal activity in both PO and MD thalamus. We show that SCI-pain can be reduced by stimulating the motor cortex, and demonstrate that this effect occurs through cortical inputs to ZI, thereby enhancing ZI inputs to PO and MD. These results support the hypothesis that SCI-pain results from reduced activity in ZI which corresponds with increased activity in thalamic nuclei involved with both sensory aspects of pain (PO) and affective aspects of pain (MD). Further, they provide evidence that MCS reverses sensory and affective components of pain by activating the incerto- thalamic pathway and highlight a novel pathway for clinical intervention.
    • Regulatory Mechanisms of the Posterior Nucleus of Thalamus and Their Contributions to Pain After Spinal Cord Injury

      Park, Anthony Sungwook; Keller, Asaf (2016)
      For patients suffering from spinal cord injury (SCI), chronic pain is one of the most debilitating aspect of the disorder. As many as 80% of patients with SCI eventually develop chronic pain, typically described as burning, stabbing, and shooting (SCI-Pain). Such pain occurs spontaneously, and diffusely across the body, and are typically combined with enhanced pain responses to both noxious, and normally innocuous, stimuli. While the precise mechanisms underlying such pain has remained elusive, accumulating evidence implicates pathologically disinhibited thalamus. The posterior nucleus of thalamus (PO) is a higher-order somatosensory nucleus thought to be specialized in processing nociceptive information, and prior work from our laboratory has shown that activity in PO is dramatically increased in SCI-Pain. This hyperactivity, in turn, was found to be mediated by pathological suppression of inhibition from the zona incerta (ZI; this forms the incerto-thalamic circuit), an inhibitory nucleus that sends powerful GABAergic afferents to PO and mediates both tonic and feed-forward inhibition. Notably, inactivation of ZI results in immediate and profound hyperalgesia in naive rats, along with a concomitant increased activity of thalamic neurons while direct stimulation of ZI in SCI animals results in immediate reversal of behavioral signs of pain. Direct stimulation of ZI, however, is a highly undesirable clinical solution; instead, we endeavor to discover molecular targets for interventions, and to this end, examine synaptic mechanisms regulating PO activity. In Chapter 1, we develop a biophysically realistic in silico model of the incerto-thalamic circuit, generating several critical predictions. Among them, the most insightful predictions were 1) that spontaneous PO activity is preferentially regulated by GABABR-mediated mechanisms, while evoked activity is preferentially regulated by GABAAR, and 2) that modulation of presynaptic GABA release an effective means to regulate the incerto-thalamic circuit. In Chapter 2, we experimentally test the second prediction that modulation of presynaptic release is an effective regulatory mechanism in PO, and demonstrate several potential mechanisms by which presynaptic regulation occurs. In Chapter 3, we test whether regulatory mechanisms of presynaptic release are altered in SCI-Pain, and show evidence of pathological alterations in regulatory mechanisms of presynaptic release mediated by GABAB receptors.