Temi, S., Rudyk, C., Armstrong, J., Landrigan, J., Dedek, C., Salmaso, N., Hildebrand, M.E. (2021) Differential expression of GluN2 NMDA receptor subunits in the dorsal horn of male and female rats. Channels. 15(1): 179-192.
Despite essential roles of NMDARs in physiological and pathological pain processing, the distribution and function of specific GluN2 NMDAR subunits across dorsal horn laminae remain poorly understood, especially in females. Here we find a preferential localization of GluN2B and GluN2D to the pain processing superficial dorsal horn (SDH) of male rats. In female rats, only GluN2B is localized to the SDH, revealing a sex difference in baseline excitatory synaptic signalling within spinal nociceptive circuits. Most striking, we find that GluN2B NMDARs are preferentially localized to medial regions of the SDH, but only in males. This asymmetry in NMDAR subunit localization across mediolateral SDH axis suggests potential distinct mechanisms of plasticity and neuronal integration across SDH pain networks, which further diverges between males and females.
Mahmoud H, Martin N, Hildebrand ME. (2020). Conserved contributions of NMDA receptor subtypes to synaptic responses in lamina II spinal neurons across early postnatal development. Molecular Brain, 13, 31.
At brain synapses, there is a switch from slow GluN2B-mediated NMDA receptors to faster GluN2A-dominated NMDA receptors as well as an increase in the ratio of AMPA to NMDA receptors during early postnatal development. To test whether this developmental switch occurs within pain processing spinal cord neurons, we characterized excitatory synaptic responses from lamina II dorsal horn neurons of one to three week-old rats. Surprisingly, we found that the molecular identity of NMDA receptor responses (predominantly GluN2B and GluN2A) as well as the relative contribution of AMPA receptors versus NMDA receptors did not change at lamina II synapses across early postnatal development (P7 to P21). The lack of a molecular switch and persistence of slow-decaying GluN2B- and GluN2D-mediated synaptic responses throughout neuronal maturation in the dorsal horn has implications for understanding both the regulation of synaptic glutamatergic receptors as well as spinal mechanisms of pain processing.
Dedek A, Xu J, Kandegedara, Lorenzo LE, Godin AG, De Koninck Y, Lombroso PJ, Tsai EC, Hildebrand ME. (2019). Loss of STEP61 couples disinhibition to N-methyl-D-aspartate receptor potentiation in rodent and human spinal pain processing. Brain, Volume 142, Issue 6, Pages 1535–1546.
The tyrosine phosphatase STEP61 is the molecular brake that is lost to drive a coupling between KCC2-dependent disinhibition and the potentiation of GluN2B NMDARs in a pathological spinal mechanism that is conserved between rodent and human models of chronic pain. The ex vivo human BDNF model developed in this paper helps form a translational bridge between rodents and humans for identification and validation of novel molecular pain targets.
Hildebrand ME, Xu J, Dedek A, Li Y, Sengar AS, Beggs S, Lombroso PJ, Salter MW. (2016). Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing. Cell Rep. 17(10): 2753-65.
In this study, we have uncovered a new mechanism that leads to increased spinal excitation and pain hypersensitivity. We show that two separate spinal mechanisms are actually linked so that taking a foot off the brakes (BDNF-mediated loss of synaptic inhibition) directly causes a stepping on the gas (increase in excitatory NMDAR responses) in dorsal horn neurons after nerve injury. This pathological mechanism may be the root cause of many chronic pain conditions.
Hildebrand, ME, Pitcher, GM, Harding, EK, Li, H, Beggs, S, Salter, MW. (2014). Dominant GluN2B- and GluN2D-mediated synaptic responses in the adult spinal cord. Scientific Reports 4: 4094 (12 pages).
In this paper, we characterized the molecular and biophysical properties of synaptic NMDA receptors (NMDARs) in lamina I dorsal horn neurons of the adult rat. Unlike GluN2A-dominated responses at most adult CNS synapses, we found that slow GluN2B- and GluN2D-containing receptors dominate synaptic NMDAR responses at adult lamina I synapses. The results of this study are relevant for both the pain and NMDAR research communities, and it identifies GluN2D as a new potential molecular target for treating pain.
Bourinet, E, Altier, C, Hildebrand, ME, Trang, T., Salter, MW, Zamponi, GW. (2014). Calcium permeable ion channels in pain signaling. Physiological Reviews 94(1): 81-140. URL: http://www.ncbi.nlm.nih.gov/pubmed/24382884
In this comprehensive review, we outline the roles of calcium-permeable ion channels, including voltage-gated calcium channels and synaptic NMDA receptors, in physiological and pathological mechanisms of pain processing, with particular emphasis on peripheral nociceptors and spinal cord dorsal horn neurons.
Hildebrand ME, Mezeyova J, Smith PL, Salter MW, Tringham E, Snutch TP. (2011a). Identification of sodium channel isoforms that mediate action potential firing in lamina I/II spinal cord neurons. Molecular Pain 7(1): 67 (13 pages).
Here, we investigated the molecular, biophysical, and pharmacological properties of voltage-gated sodium channels in superficial dorsal horn neurons. By combining quantitative real-time PCR with the spinal cord slice recording assay, we discovered that the identity and functional properties of voltage-gated sodium channels expressed in the spinal cord dorsal horn is very distinct from those expressed in peripheral pain-sensing neurons. Thus, dorsal horn sodium channels may represent a promising molecular target for future pain therapeutics.
Hildebrand ME, Smith P, Bladen C, Eduljee C, Xie J, Chen L, Fee-Maki M, Doering C, Mezeyova J, Zhu Y, Belardetti F, Pajouhesh H, Parker D, Parmar M, Porreca F, Tringham E, Zamponi G, Snutch TP. (2011b). A novel slow inactivation specific ion channel modulator attenuates neuropathic pain. Pain 152(4): 833-843.
As part of a multidisciplinary preclinical research team at Zalicus Pharmaceuticals, we identified a novel class of analgesics that potently reverse chronic pain by acting on pathological states of excitatory voltage-gated channels. This paper is part of a shift in the ion channel drug discovery field from a sole focus on specificity against individual channel subtypes to specificity against pathological function across channel classes.
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