Diabetic neuropathy affects approximately 30% of patients with diabetes mellitus with many patients experiencing severe and unremitting spontaneous pain. In addition diabetic patients frequently exhibit abnormal stimulus-evoked pains, including an increased responsiveness to noxious stimuli (hyperalgesia) as well as a hyper-responsiveness to normally innocuous stimuli (allodynia). Unfortunately, the mechanisms of chronic neuropathic pain (CNP) in diabetes are not clear. However, there is increasing evidence that altered central nervous system (CNS) processing plays a key role in the development of chronically painful conditions. Accordingly, we propose to identify CNS mechanisms of chronic neuropathic pain (CNP) in diabetes, by combining behavioral pain assessment with functional brain imaging in the streptozotocin (STZ) diabetic rat model. We hypothesize that a significant proportion of STZ-diabetic rats will develop behavioral indices of a chronic neuropathic pain state, including mechanical allodynia and thermal hyperalgesia. We propose that as a consequence of and/or in parallel to the development of a diabetic neuropathy, maladaptive alterations occur in the functional activation of multiple CNS structures involved in pain perception and/or pain modulation. We propose to identify pain-related increases in the baseline (unstimulated) and stimulus-evoked activation of specific cortical (SI, SII, CC and RS) and thalamic (VPL and AD) brain regions in diabetic rats that correlate with the development of CNP. Furthermore we hypothesize that these pain-specific increases in activation within the above cortical and thalamic structures are not merely a reflection of abnormal input from peripheral and spinal levels, but that these supraspinal structures actively participate to produce and/or maintain the neuropathic pain state. Finally, we propose that CNP in diabetes mellitus is due not only to activation of specific thalamic and cortical structures involved in processing nociceptive input, but is also due to the concurrent deactivation of the brainstem periaqueductal gray (PAG), a brain region involved in endogenous antinociception. This research promises to identify critical supraspinal mechanisms of chronic neuropathic pain in diabetes mellitus. ? ?
| Harte, Steven E; Meyers, Jessica B; Donahue, Renee R et al. (2016) Mechanical Conflict System: A Novel Operant Method for the Assessment of Nociceptive Behavior. PLoS One 11:e0150164 |
| Paulson, Pamela E; Wiley, John W; Morrow, Thomas J (2007) Concurrent activation of the somatosensory forebrain and deactivation of periaqueductal gray associated with diabetes-induced neuropathic pain. Exp Neurol 208:305-13 |
