Role of Gaq/11 signaling in activity-dependent peripheral sensitization
Final Report Abstract
G-protein coupled receptor (GPCR) signaling plays a major role in the body. The signaling pathways are important for nociceptive modulation and the generation of pain. Various nociceptive modulators activate GPCRs that are capable to bind Gq/11, Gs, Gi/o and/or G12/13 G-proteins. The individual contribution and impact of the different G-protein signaling branches on the modulation of nociceptor function in vivo is unknown. Using nociceptor specific Gαq/11-deficient mice we have recently found a tonic basal nociceptor modulation, a contribution to inflammatory pain and modulatory effects on voltage-gated sodium-channels. Based upon these findings we aimed at analysing the underlying mechanisms and relevance of this signaling branch in different projects. lthough Gαq and Gα11 are nearly ubiquitously expressed, the specific contribution of the individual G-proteins towards nociceptor sensitization is unknown. We generated mice that were nociceptorspecific deficient for either Gαq, Gα11 or both G-proteins. Mechanical- and heat-sensitivity was measured upon intraplantar application of various algogens and agonists that are known to activate different G-protein GPCR signaling branches. We found that the Gαq/11 signaling pathway contributes significantly to mechanical allodynia elicited via a broad range of inflammatory mediators and that heat hyperalgesia is mediated via distinct G-protein GPCRs or other receptors. Additionally we found a predominant role for Gαq- over Gα11-proteins in nociceptive neurons. These results constitute a valuable tool for studying known nociceptor mediators and analyse the mechanisms of action of new mediators in pain sensitization. Gq rather than G11 preferentially mediates nociceptor sensitization. Downstream mediators of the Gαq/11 signaling branch are known to modulate gene transcription but the contribution of Gαq/11 on gene regulation in nociceptive neurons is unknown. Using ‘Deep sequencing’ we analyse genes in the DRGs of control and SNS-Gq/11 mice under basal and inflammatory conditions. We found several known and novel pro-and anti-nociceptive genes to be regulated in Gαq/11 deficient mice. The targets are useful to understand the significance of the Gαq/11 signaling branch and constitute valuable tools to develop future therapeutic approaches for different clinically relevant disease conditions. Many GPCRs and their ligands are involved in cancer initiation and progression. We investigated the contribution of the Gαq/11 signaling in a tumor-induced pain model. Gαq/11 deficient mice showed significantly reduced mechanical and heat hypersensitivity and ongoing experiments will give insights into tumor-induced hypertrophy, peripheral nerve sprouting and potential therapeutic targets. Most preclinical pain models rely on short duration stimulus-evoked measurements even though chronic pain is usually a day and night experience that is mostly characterized by spontaneous and ongoing pain. Therefore, we were interested to establish non-evoked measures to assess changes in the animal wellbeing as readout for the affective component of pain and spontaneous pain. We used a portfolio of classical stimulus-evoked measures, gait analyses, long-term observer-independent voluntary wheel running and homecage monitoring in two classical pain models; the inflammatory Complete Freund´s Adjuvans (CFA) model and the neuropathic spared nerve injury (SNI) model under different social housing conditions. The CFA model provoked changes in wheel running and homecage activity. Stimulus-evoked hypersensitivity lasted longer than gait abnormalities and decreased wheel running activity in both social housing conditions. In the SNI model we found timely correlations between evoked hypersensitivity and changes in most gait parameters. Some dynamic gait parameters were changed time-dependently. SNI mice did not showed tremendous alterations in home cage activity. Wheel running activity was not affected in SNI mice, but by social isolation. These results provide fundamental considerations for experimental planning and discussion of painrelated behavioral changes. Studying ongoing and spontaneous pain in rodents-challenges and opportunities. Voluntary and evoked behavioral correlates in neuropathic pain states under different housing conditions. Voluntary and evoked behavioral correlates in inflammatory pain conditions under different social housing conditions.
Publications
- (2013) Gq rather than G11 preferentially mediates nociceptor sensitization. Molecular Pain. 9:54
Wirotanseng LN, Kuner R, Tappe-Theodor A
(See online at https://doi.org/10.1186/1744-8069-9-54) - (2014) Studying ongoing and spontaneous pain in rodents - challenges and opportunities. European Journal of Neuroscience. 39(11):1881-90
Tappe-Theodor A, Kuner K
(See online at https://doi.org/10.1111/ejn.12643) - (2016) Voluntary and evoked behavioral correlates in inflammatory pain conditions under different social housing conditions. Pain Report 1-1-p e564
Pitzer C, Kuner R, Tappe-Theodor A
(See online at https://doi.org/10.1097/PR9.0000000000000564) - (2016) Voluntary and evoked behavioral correlates in neuropathic pain states under different housing conditions. Molecular Pain. 15;12
Pitzer C, Kuner R, Tappe-Theodor A
(See online at https://doi.org/10.1177/1744806916656635)
