Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons

Abstract

Abstract Background The therapeutic failure in the management of chronic inflammatory pain in geriatric populations arises from drug-associated toxicity and lack of specific regulation of nociceptor excitability. Methods We compared 6 and 24 months-old female Wistar rats that underwent cutaneous inflammation to examine the role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in long-term inflammatory pain. We carried out this using a combination of behavioral pain assessments, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA, and the in vitroevaluation of cytokine effects. Results Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1β up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1β had this effect only on young and aged neurons, respectively. Conclusion Our findings demonstrate that inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.