Vjekoslav Miletic

 

 

Spinal Plasticity in the Development of Chronic Pain

E-mail: vmiletic@wisc.edu

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., 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 [PDF]
• Miyabe, T., G. Miletic, and V. Miletic. 2006. Loose ligation of the sciatic nerve in rats elicits transient up-regulation of Homer1a gene expression in the spinal dorsal horn. Neurosci. Lett. 398: 296-299 [PDF]
• Miyabe, T., G. Miletic, and V. Miletic. 2005. Early activation of cyclic AMP response element binding protein (CREB) following loose ligation of the sciatic nerve in rats. Thalam. Rel. Sys. 3:19-23
• Miletic, G., P. Draganic, M.T. Pankratz, and V. Miletic. 2003. Muscimol prevents long-lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury exhibiting decreased levels of the GABA transporter GAT-1. Pain 105: 347-353.
• Miletic, G., M.T. Pankratz, and V. Miletic. 2002. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany neuropathic pain following chronic constriction injury in rats. Pain 99: 493-500. [PDF]
• Miletic, G. and V. Miletic. 2002. Increases in the concentration of brain derived neurotrophic factor (BDNF) in the lumbar spinal dorsal horn are associated with pain behavior following chronic constriction injury in rats. Neurosci. Lett. 319: 137-140. [PDF]
• Draganic, P., G. Miletic, and V. Miletic. 2001. Changes in post-tetanic potentiation of A-fiber dorsal horn field potentials parallel the development and disappearance of neuropathic pain after sciatic nerve ligation in rats. Neurosci. Lett. 301: 127-130. [PDF]
• Miletic, G. and V. Miletic. 2001. Contribution of GABAA receptors to metaplasticity in the spinal dorsal horn. Pain 90: 157-162. [PDF]
• Miletic, G. and V. Miletic. 2000. Long-term changes in sciatic-evoked A-fiber dorsal horn field potentials accompany loose ligation of the sciatic nerve in rats. Pain 84: 353-359. [PDF]