Vjekoslav Miletic

 

 

Spinal Plasticity in the Development of Chronic Pain

E-mail: vmiletic@wisc.edu

Office Phone: (608) 263-1238, (608) 263-1239

Research Strengths: Development: Plasticity and Repair

Our overall goal is to elucidate some of the mechanisms underlying the pathophysiology of chronic pain. Recent studies indicate that perhaps one such mechanism is long-lasting synaptic plasticity in the spinal dorsal horn. In the brain, synaptic plasticity may enable learning and memory. In the dorsal horn, however, it may lead to an undesirable transformation of the essential but rapidly terminated sensation of acute pain into unproductive persistent pain. We are using the loose ligation of the sciatic nerve model in rats, and are presently focusing on the potential contribution of potassium-chloride co-transporter 2 (KCC2), Homer 1a/1b/1c and Shank 1 and 2. KCC2 is an important mediator of GABA-dependent inhibition, and Homer and Shank are postsynaptic density scaffolding proteins. All of these proteins may play critical roles in promoting enhanced synaptic efficacy following sciatic nerve injury. The identification of some of the contributors to spinal long-lasting plasticity should allow the development of novel, mechanistically-based analgesic treatments to prevent or abolish chronic pain, and minimize or eliminate patient suffering.

Selected Publications:

• Miletic G, Dumitrascu CI, Honstad CE, Micic D, Miletic V. Loose ligation of the rat sciatic nerve elicits early accumulation of Shank1 protein in the postsynaptic density of spinal dorsal horn neurons. Pain, 2010, 149:152-159, PMID: 20171009.
• Miletic G, Driver AM, Miyabe T, Miletic V. Early changes in Homer1 proteins in the spinal dorsal horn are associated with loose ligation of the rat sciatic nerve. Anesth Anal 2009, 109:2000-2007, PMID: 19923532.
• Miletic, G., and V. Miletic. 2008. Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn. Pain 137: 532-539
• Shih A, Miletic V, Miletic G, Smith LJ. Systemic benzodiazepine administration reverses thermal hyperalgesia and prevents GABA transporter loss in the rodent chronic constriction injury model of neuropathic pain. Anesth Anal 2008, 106:1296-1302, PMID: 18349209.