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The IASP Pain Research Forum will host a seminar with Michael Hildebrand, PhD,
Carleton University, Canada.
A Q&A session moderated by Sascha Alles, PhD, University of New Mexico School of Medicine, USA, will follow the presentation.
Here is an abstract from Dr. Hildebrand:
The superficial dorsal horn (SDH) of the spinal cord is an essential component of the pain transmission and regulation pathway. Changes in excitability within the SDH nociceptive network can lead to chronic pain, and yet even the basic electrical properties of subpopulations of these critical pain processing neurons remain to be characterized. Despite essential roles of excitatory NMDA receptors (NMDARs) in physiological and pathological pain processing, the distribution and function of specific NMDAR subunits across dorsal horn laminae remain poorly understood. Moreover, what is known for NMDAR expression and function in both the brain and spinal cord is largely based on studies using male (often juvenile) rodents.
To bridge the translational divide and develop better treatments for pain in humans, foundational knowledge is required on what specific types of receptors shape SDH pain processing across development, sex and species. In this talk, I will highlight work in our lab investigating the expression, function, and regulation of NMDARs in subpopulations of SDH neurons in both male and female rats as well as in humans.
In contrast to brain synapses, where there is a switch from slow GluN2B-mediated NMDARs to faster GluN2A-dominated NMDARs during the first weeks of postnatal development, we have found that GluN2B and GluN2A contribute equally to lamina II synaptic responses across early rodent development, with a small contribution from GluN2D as well. Using immunohistochemical approaches, we found a preferential localization of GluN2B and GluN2D to the SDH of juvenile male rats. In female rats, only GluN2B is localized to the SDH, revealing a sex difference in baseline NMDAR signalling within developing spinal nociceptive circuits. In recordings of functional NMDAR responses from adult lamina I neurons, we discovered a high heterogeneity in the biophysical properties of synaptic NMDAR responses within individual neurons, which is highly conserved across sex in both rats and humans.
Finally, I will discuss a mechanism of NMDAR dysregulation by a BDNF/KCC2/STEP61/Fyn pathway that is conserved from rodent to human models of pathological pain, but that is sexually dimorphic and repressed by the organizational effects of female sex hormones during development. These discoveries provide steps towards the understanding and treatment of spinal pain pathology in both males and females.