Some of our current graduate students have provided descriptions of their research projects that offer insights into the work taking place in their laboratories.
The sensation of pain is initiated by activation of nociceptors and transmission of information into the dorsal horn of the spinal cord via primary afferent neurons. The cell bodies of these neurons lie in the dorsal root ganglia (DRG) and their terminals reside primarily in the superficial laminae of the dorsal horn.
Classical analgesics such as morphine are thought to reduce the release of excitatory neurotransmitters from these primary afferent terminals and to thereby impair the transmission of noxious information into the central nervous system. Studying classical analgesics forms one aspect of my project. In particular I investigate the hypothesis that suppression of Ca2+ current in primary afferent terminals does not completely account for the ability of opioids to suppress neurotransmitter release. (This hypothesis is based on recent work in the Smith lab.)
The other part of my project involves studying a specific type of pain known as 'neuropathic pain' that is caused by damage to the central nervous system. Neuropathic pain is a major clinical problem as it is almost always chronic and frequently intractable. It is estimated that 2 to 3% of the population in the developed world suffers from neuropathic pain, which equates to approximately one million Canadians that have this devastating condition. The onset of many types of neuropathic pain involves altered expression of ion channels in DRG neurons and altered synaptic transmission in the spinal dorsal horn. Since the relationship between altered expression of Ca2+ channels in DRG cell bodies and alterations in neurotransmitter release are poorly understood, I monitor Ca2+ dynamics in primary afferent terminals under conditions of neuropathic pain such chronic constriction injury (CCI) in rats.
My experiments involve the use of 1) Ca2+ imaging in live tissue using confocal microscopy and the genetically encoded fluorescent Ca2+ indicator protein gCaMP or AM dyes such as Fluo-4 and 2) whole cell patch clamp recording from DRG and substantia gelatinosa neurons in the spinal dorsal horn.
This work will provide important new insights into the action of classical analgesics and into the etiology of neuropathic pain.Recent Publications
I. Introduction: Heart failure is associated with changes in energy metabolism, but there is no agreement on the nature and consequences of these alterations. One theory suggests that the failing heart is in an energetic crisis where rates of energy metabolism are insufficient to meet normal energy demands, while a second theory concerns the inefficient utilization of energy for mechanical function. Recently, modulation of energy substrate metabolism has been considered as a new approach in the treatment of heart failure.
II. Hypothesis: Optimizing energy substrate metabolism in failing hearts will 1) improve cardiac mechanical function, 2) limit ischemia reperfusion injury, and 3) slow the progression of adverse remodeling in heart.
III. Objectives: a) To compare energy metabolism in normal and failing hearts. We will characterize the molecular basis for these differences in mouse hearts subjected to coronary artery ligation and then relate them to the observed changes in mechanical function. This will help us determine whether metabolic changes in heart failure help improve left ventricular function or are maladaptive and worsen heart function. b) To examine the ability of drug-induced metabolic modulation to improve mechanical function of failing hearts ex vivo. Metabolic modulators will be used to assess the impact of improving the coupling between glycolysis and glucose oxidation and whether this lessens left ventricular dysfunction.
IV. Methodology: We use echocardiography to assess cardiac function in vivo in mouse hearts that are either normal or that have been remodeled following coronary artery ligation. Left ventricular work and rates of energy metabolism are assessed in vitro using hearts perfused in working mode.
V. Significance: These studies will provide new information about whether left ventricular dysfunction in heart failure is due to energy deficiency and/or inefficiency in energy utilization. By examining the mechanisms and consequences of altered substrate metabolism, we hope to identify novel targets for pharmacological manipulation that via future in vivo validation, will translate to clinical practice to aid in the clinical management of heart failure.