Up‐regulation of oxytocin receptors on peripheral sensory neurons mediates analgesia in chemotherapy‐induced neuropathic pain

Abstract

Background and Purpose Chemotherapy‐induced neuropathic pain (CINP) currently has limited effective treatment. Although the roles of oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP. Experimental Approach Paclitaxel (PTX) was used to establish CINP. Quantitative real‐time polymerase chain reaction (qRT‐PCR), in situ hybridization, and immunohistochemistry were used to observe OXTR expression in dorsal root ganglia (DRG). The antinociceptive effects of OXT were assessed by hot‐plate and von Frey tests. Whole‐cell patch clamp was performed to record sodium currents, excitability of DRG neurons, and excitatory synapse transmission. Key Results Expression of OXTR in DRG neurons was enhanced significantly after PTX treatment. Activation of OXTR exhibited antinociceptive effects, by decreasing the hyperexcitability of DRG neurons in PTX‐treated mice. Additionally, OXTR activation up‐regulated the phosphorylation of protein kinase C (pPKC) and, in turn, impaired voltage‐gated sodium currents, particularly the voltage‐gated sodium channel 1.7 (NaV1.7) current, that plays an indispensable role in PTX‐induced neuropathic pain. OXT suppressed excitatory transmission in the spinal dorsal horn as well as excitatory inputs from primary afferents in PTX‐treated mice. Conclusion and Implications The OXTR in small‐sized DRG neurons is up‐regulated in CINP and its activation relieved CINP by inhibiting the neural excitability by impairment of NaV1.7 currents via pPKC. Our results suggest that OXTR on peripheral sensory neurons is a potential therapeutic target to relieve CINP.

Oxytocin and corticotropin‐releasing hormone exaggerate nucleus tractus solitarii neuronal and synaptic activity following chronic intermittent hypoxia

“…Together, these results and others suggest the influence of OT depends on the neural phenotype, synapse order and the induced signalling cascades. OTRs influence both central and peripheral neurons (Barberis et al., 1992; Li et al., 2023) that impact cardiovascular regulation, stress responsiveness and the neuroinflammatory cascade (Szczepanska‐Sadowska et al., 2021). Our data extends these results to demonstrate an excitatory influence of OT via pre‐ and postsynaptic mechanisms within nTS circuits after CIH where the autonomic dysfunction and heightened sympathetic tone are common (Jameson et al., 2016).…”

Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy

“…The hot plate test determines thermal hyperalgesia by measuring the nociceptive latency to lick a hindpaw or jump out of the enclosure when the mice or rats are placed on a metal surface with a constant temperature (50–55°C). To prevent prolonged exposure to noxious stimuli and minimize the risk of tissue damage to the hindpaw, a cut-off time of 20–40 s is commonly used ( Deuis et al, 2017 ; Al-Romaiyan et al, 2023 ; da Motta et al, 2023 ; Li et al, 2023 ). Alternatively, the nociceptive threshold can be measured by counting the total number of flinches over a period of time at a given temperature ( Deuis et al, 2013 ).…”

The psychophysiology of music-based interventions and the experience of pain

“…These rhythmic patterns of synchronized neural activity flowing within and across, and linking, neighboring regions of the brain have different repetitive frequencies (delta,(1)(2)(3)(4)theta,(4)(5)(6)(7)(8)alpha,(8)(9)(10)(11)(12)(13)beta,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)gamma,, each associated with different brain states. Interestingly, there is evidence that oscillatory brain activity is linked to pain perception (Ploner and Gross, 2019;Kenefati et al, 2023;Li et al, 2023b). Pain-induced changes in gamma oscillations in somatosensory cortex have been described (Gross et al, 2007), while noxious heat stimulation in healthy subjects was shown to increase gamma wave activity in bilateral mPFC but decrease alpha and beta wave activity in somatosensory cortex (Nickel et al, 2017).…”