Abstract
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.
Highlights
Pain arising from peripheral tissue and/or nerve injury is driven by activity in nociceptors [1,2,3]
Taken together with our observations (Fig 1M), that more than 90% of the Sp4+ neurons measured less than 400 μm2, supports the idea that transcription factor Sp4 is expressed in a subpopulation of nociceptive neurons in the Dorsal Root Ganglion (DRG)
In support of Sp4 playing a critical role in the regulation of peripheral pain transduction, we examined the neurochemical characteristics of Sp4-positive lumbar DRG neurons using antisera to TRPV1 and isolectin B4 (IB4), established markers of primary afferent nociceptors, [80] as well as anti-neurofilament 200kD (NF200) and anti-peripherin antibodies [65]
Summary
Pain arising from peripheral tissue and/or nerve injury is driven by activity in nociceptors [1,2,3]. Studies linking an increase in the expression of TRP channels support tissue-injury induced changes in nociceptor transcription of TRPV1 to profoundly affect nociceptor signaling [13,14,15]. We have previously characterized transcriptional control elements responsible for the expression of TRPV1 in nociceptors [16, 17] This analysis revealed a TRPV1 dual promoter system (P1 and P2) that is positively regulated by Nerve Growth Factor (NGF) [17]. Two members of the Sp1-like transcription factor family, Sp4 and to a lesser extent Sp1, bind to the TRPV1 P2 promoter domain and are proposed to positively regulate TRPV1 expression [18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
