Research Article: Transcription factor Sp4 is required for hyperalgesic state persistence

Date Published: February 27, 2019

Publisher: Public Library of Science

Author(s): Kayla Sheehan, Jessica Lee, Jillian Chong, Kathryn Zavala, Manohar Sharma, Sjaak Philipsen, Tomoyuki Maruyama, Zheyun Xu, Zhonghui Guan, Helge Eilers, Tomoyuki Kawamata, Mark Schumacher, Alexander G. Obukhov.


Understanding how painful hypersensitive states develop and persist beyond the initial hours to days is critically important in the effort to devise strategies to prevent and/or reverse chronic painful states. Changes in nociceptor transcription can alter the abundance of nociceptive signaling elements, resulting in longer-term change in nociceptor phenotype. As a result, sensitized nociceptive signaling can be further amplified and nocifensive behaviors sustained for weeks to months. Building on our previous finding that transcription factor Sp4 positively regulates the expression of the pain transducing channel TRPV1 in Dorsal Root Ganglion (DRG) neurons, we sought to determine if Sp4 serves a broader role in the development and persistence of hypersensitive states in mice. We observed that more than 90% of Sp4 staining DRG neurons were small to medium sized, primarily unmyelinated (NF200 neg) and the majority co-expressed nociceptor markers TRPV1 and/or isolectin B4 (IB4). Genetically modified mice (Sp4+/-) with a 50% reduction of Sp4 showed a reduction in DRG TRPV1 mRNA and neuronal responses to the TRPV1 agonist—capsaicin. Importantly, Sp4+/- mice failed to develop persistent inflammatory thermal hyperalgesia, showing a reversal to control values after 6 hours. Despite a reversal of inflammatory thermal hyperalgesia, there was no difference in CFA-induced hindpaw swelling between CFA Sp4+/- and CFA wild type mice. Similarly, Sp4+/- mice failed to develop persistent mechanical hypersensitivity to hind-paw injection of NGF. Although Sp4+/- mice developed hypersensitivity to traumatic nerve injury, Sp4+/- mice failed to develop persistent cold or mechanical hypersensitivity to the platinum-based chemotherapeutic agent oxaliplatin, a non-traumatic model of neuropathic pain. Overall, Sp4+/- mice displayed a remarkable ability to reverse the development of multiple models of persistent inflammatory and neuropathic hypersensitivity. This suggests that Sp4 functions as a critical control point for a network of genes that conspire in the persistence of painful hypersensitive states.

Partial Text

Pain arising from peripheral tissue and/or nerve injury is driven by activity in nociceptors [1–3]. Depending on the inciting event (inflammation, nerve injury), not only peripheral but also spinal and/or supraspinal signaling pathways can all conspire to amplify and produce persistence of pain [4–6]. At the level of the nociceptor, the basis of acute inflammatory pain and its persistence has been studied with a focus on inflammation-induced modifications of ion channel function that result in lowering activation thresholds in the presence of the ongoing production of endogenous sensitizing molecules [3, 7, 8]. However, other processes that drive the persistence and transition from acute to chronic pain continue to be examined [5, 9–12].

Our findings suggest that the ability of certain hyperalgesic states to persist for days to weeks is dependent on the abundance and presumed activity of transcription factor Sp4. We propose that the expressed level of TRPV1 during an inflammatory state which is positively regulated by Sp4, is required for the persistence of inflammatory thermal hyperalgesia. Depending on the inflammatory and/or neuropathic condition, we also propose that Sp4 serves a broader role, beyond the regulation of TRPV1, in the development and persistence of painful mechanical and cold hypersensitive states.

Given its expression in a subset of small to medium sized DRG neurons with nociceptor markers, transcription factor Sp4 is well positioned to regulate nociceptor genes that engender critical roles in the control of pain transduction and the persistence of hypersensitive states. Consistent with this notion, a 50% reduction of Sp4 expression resulted in a profound loss of persistent hypersensitivity across multiple behavior models of pain in the time course of hours. Although our studies initially focused on the relationship between Sp4, TRPV1 and thermal hyperalgesia, our results more broadly suggest that a larger Sp4-dependent gene network or nociceptive transcriptome exists inclusive of TRPV1, TRPA1 and TRPM8. This implies that Sp4 is a critical control point for interrupting a network of genes underlying the persistence of painful hypersensitive states.




Leave a Reply

Your email address will not be published.