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Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-β response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.

The success of mass vaccination programs against SARS-CoV-2 hinges on the public's acceptance of the vaccines. During a vaccine roll-out, individuals have limited information about the potential side-effects and benefits. Given the public health concern of the COVID pandemic, providing appropriate information fast matters for the success of the campaign. In this paper, time-trends in vaccine hesitancy were examined using a sample of 35,390 respondents from the Eurofound's Living, Working and COVID-19 (LWC) data collected between 12 February and 28 March 2021 across 28 European countries. The data cover the initial stage of the vaccine roll-out. We exploit the fact that during this period, news about rare cases of blood clots with low blood platelets were potentially linked to the Oxford/AstraZeneca vaccine (or Vaxzeveria). Multivariate regression models were used to analyze i) vaccine hesitancy trends, and whether any trend-change was associated with the link between the AstraZeneca vaccine ii) and blood clots (AstraZeneca controversy), and iii) the suspension among several European countries. Our estimates show that vaccine hesitancy increased over the early stage of the vaccine roll-out (0·002, 95% CI: [0·002 to 0·003]), a positive shift took place in the likelihood of hesitancy following the controversy (0·230, 95% CI: [0·157 to 0·302]), with the trend subsequently turning negative (-0·007, 95% CI: [-0·010 to -0·005]). Countries deciding to suspend the AstraZeneca vaccine experienced an increase in vaccine hesitancy after the suspensions (0·068, 95% CI: [0·04 to 0·095]). Trust in institutions is negatively associated with vaccine hesitancy. The results suggest that SARS-CoV-2 vaccine hesitancy increased steadily since the beginning of the vaccine roll-out and the AstraZeneca controversy and its suspension, made modest (though significant) contributions to increased hesitancy., Competing Interests: The authors have declared that no competing interests exist.

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non-small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.