Singleton, S. | Search bioRxiv

bioRxiv2024

Acute and early stress axis modulation in joint disease permanently reduces pain and emotional comorbidities

Chronic pain affects 20-30% of the population and imposes a significant socio-economic burden as it is often accompanied by substantial emotional comorbidities such as anxiety and depression. Yet, the mechanisms underlying the interactions between the sensory and emotional aspects of chronic pain remain poorly understood. Here, we investigated the role of FKBP51, a regulator of the stress response, in mediating both sensory and emotional symptoms of chronic pain. Inhibition of FKBP51, via genetic deletion or pharmacological blockade, in persistent joint pain reduced fast-onset sensory, functional and activity-related symptoms, as well as late anxio-depressive comorbidities. FKBP51 inhibition after the establishment of the hypersensitive state provided only temporary symptoms relief, while acute inhibition at disease onset protected from the full development of sensory and anxio-depressive symptoms for up to 6 months. Our results also indicated that early pain symptoms could predict the late sensory and emotional outcomes of chronic pain. RNA sequencing of spinal cord tissue revealed that late FKBP51 inhibition transiently altered nociceptive genes associated with mechanical hypersensitivity. In contrast, early inhibition persistently downregulated the Naaa gene, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our results indicate that early FKBP51 inhibition after injury can persistently reduce chronic pain and prevent the onset of associated emotional comorbidities by modulating critical spinal neurobiological pathways that play pivotal roles in the transition to chronic pain. Significance statementOur study reveals that early inhibition of FKBP51, a modulator in the stress axis, at the onset of joint damage provides sustained pain relief and significantly delays or prevents emotional comorbidities in a sex-dependent manner. In contrast, FKBP51 inhibition initiated after chronic pain is established results in only temporary symptoms improvement. These findings highlight a critical therapeutic window during which timely intervention can prevent the transition from acute to chronic pain. By establishing a predictive link between early therapeutic response and long-term outcomes, this work has important clinical implications for proactive and personalized chronic pain management.

neuroscience↗

bioRxiv2022

Morphine-induced mechanical hypersensitivity in mice requires delta receptors, beta-arrestin2 and c-Src activity

BackgroundMorphine diminishes acute pain, but long-term use is compromised by tolerance and hyperalgesia. Studies implicate {delta} receptors, {beta}-arrestin2 and Src kinase in tolerance. We examined whether these proteins are also involved in morphine-induced hypersensitivity (MIH). A common pathway for tolerance and hypersensitivity may provide a single target to guide improved analgesic approaches. MethodsWe examined mechanical sensitivity using automated von Frey in wild type (WT) and transgenic male and female C57Bl/6 mice before and after hind paw inflammation by complete Freunds adjuvant (CFA). We explored the expression of opioid genes in the spinal cord using quantitative RT-PCR. ResultsCFA-evoked hypersensitivity ceased on day 7 in WT mice but persisted in -/- mice. Recovery was delayed until day 13 in {delta}-/- mice. Restoration to basal sensitivity in WT mice occurred with increased {delta} expression. By contrast, {kappa} expression was reduced, while remained unchanged. Daily morphine reduced hypersensitivity in WT mice on day 3 compared to controls, however hypersensitivity recurred on day 9 and beyond. By contrast, WT mice had no recurrence of hypersensitivity in the absence of daily morphine. We used {beta}-arrestin2-/-, {delta}-/- and Src inhibition by dasatinib in WT mice to establish whether these approaches, which diminish tolerance, also attenuate MIH. While none of these approaches affected CFA-evoked inflammation or acute hypersensitivity, all caused sustained morphine anti-hypersensitivity, abolishing MIH. ConclusionsLike morphine tolerance, MIH in this model requires {delta} receptors, {beta}-arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance-induced reduction in endogenous opioid signalling.

physiology↗