Physiology Commons^™

Intravesical Cd74 And Cxcr4, Macrophage Migration Inhibitory Factor (Mif) Receptors, Mediate Bladder Pain, Shaojing Ye, Fei Ma, Dlovan F. D. Mahmood, Katherine L. Meyer-Siegler, Raymond E. Menard, David E. Hunt, Lin Leng, Richard Bucala, Pedro L. Vera

Physiology Faculty Publications

BACKGROUND: Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo.

METHODOLOGY/PRINCIPAL FINDINGS: We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary …

Considerations For Studying Sex As A Biological Variable In Spinal Cord Injury, Andrew N. Stewart, Steven M. Maclean, Arnold J. Stromberg, Jessica P. Whelan, William M. Bailey, John C. Gensel, Melinda E. Wilson

Physiology Faculty Publications

In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury (SCI) patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of …

Methylglyoxal Requires Ac1 And Trpa1 To Produce Pain And Spinal Neuron Activation, Ryan B. Griggs, Don E. Laird, Renee R. Donahue, Weisi Fu, Bradley K. Taylor

Physiology Faculty Publications

Methylglyoxal (MG) is a metabolite of glucose that may contribute to peripheral neuropathy and pain in diabetic patients. MG increases intracellular calcium in sensory neurons and produces behavioral nociception via the cation channel transient receptor potential ankyrin 1 (TRPA1). However, rigorous characterization of an animal model of methylglyoxal-evoked pain is needed, including testing whether methylglyoxal promotes negative pain affect. Furthermore, it remains unknown whether methylglyoxal is sufficient to activate neurons in the spinal cord dorsal horn, whether this requires TRPA1, and if the calcium-sensitive adenylyl cyclase 1 isoform (AC1) contributes to MG-evoked pain. We administered intraplantar methylglyoxal and then evaluated …

Complement 3a Receptor In Dorsal Horn Microglia Mediates Pronociceptive Neuropeptide Signaling, Suzanne Doolen, Jennifer Cook, Maureen Riedl, Kelley Kitto, Shinichi Kohsaka, Christopher N. Honda, Carolyn A. Fairbanks, Bradley K. Taylor, Lucy Vulchanova

Physiology Faculty Publications

The complement 3a receptor (C3aR1) participates in microglial signaling under pathological conditions and was recently shown to be activated by the neuropeptide TLQP‐21. We previously demonstrated that TLQP‐21 elicits hyperalgesia and contributes to nerve injury‐induced hypersensitivity through an unknown mechanism in the spinal cord. Here we determined that this mechanism requires C3aR1 and that microglia are the cellular target for TLQP‐21. We propose a novel neuroimmune signaling pathway involving TLQP‐21‐induced activation of microglial C3aR1 that then contributes to spinal neuroplasticity and neuropathic pain. This unique dual‐ligand activation of C3aR1 by a neuropeptide (TLQP‐21) and an immune mediator (C3a) represents a …

Endogenous Opioid-Masked Latent Pain Sensitization: Studies From Mouse To Human, Manuel P. Pereira, Renee R. Donahue, Jørgen B. Dahl, Marianne Werner, Bradley K. Taylor, Mads U. Werner

Physiology Faculty Publications

Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3–10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.

Macrophage Migration Inhibitory Factor Mediates Par-Induced Bladder Pain., Dimitrios E. Kouzoukas, Katherine L. Meyer-Siegler, Fei Ma, Karin N. Westlund, David E. Hunt, Pedro L. Vera

Physiology Faculty Publications

INTRODUCTION: Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is constitutively expressed in urothelial cells that also express protease-activated receptors (PAR). Urothelial PAR1 receptors were shown to mediate bladder inflammation. We showed that PAR1 and PAR4 activator, thrombin, also mediates urothelial MIF release. We hypothesized that stimulation of urothelial PAR1 or PAR4 receptors elicits release of urothelial MIF that acts on MIF receptors in the urothelium to mediate bladder inflammation and pain. Thus, we examined the effect of activation of specific bladder PAR receptors on MIF release, bladder pain, micturition and histological changes.

METHODS: MIF release was measured …

Acid-Sensing Ion Channels And Pain, Qihai Gu, Lu-Yuan Lee

Physiology Faculty Publications

Pathophysiological conditions such as inflammation, ischemia, infection and tissue injury can all evoke pain, and each is accompanied by local acidosis. Acid sensing ion channels (ASICs) are proton-gated cation channels expressed in both central and peripheral nervous systems. Increasing evidence suggests that ASICs represent essential sensors for tissue acidosis-related pain. This review provides an update on the role of ASICs in pain sensation and discusses their therapeutic potential for pain management.