<p>Selective Ablation of Descending Serotonin from the Rostral Ventromedial Medulla Unmasks Its Pro-Nociceptive Role in Chemotherapy-Induced Painful Neuropathy</p>

Abstract

Purpose: Chemotherapy-induced painful neuropathy (CIPN) is a severe adverse effect of many anti-neoplastic drugs that is difficult to manage. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter in the rostral ventromedial medulla (RVM), which modulates descending spinal nociceptive transmission. However, the influence of the descending 5-HT from the RVM on CIPN is poorly understood. We investigated the role of 5-HT released from descending RVM neurons in a paclitaxel-induced CIPN rat model. Methods: CIPN rat model was produced by intraperitoneally injecting of paclitaxel. Pain behavioral assessments included mechanical allodynia and heat hyperalgesia. 5-HT content was analyzed by high-performance liquid chromatography (HPLC). Western blot and immunohistochemistry were used to determine tryptophan hydroxylase (Tph) and c-Fos expression. The inhibitors p-chlorophenylalanine (PCPA) and SB203580 were administrated by stereotaxical RVM microinjection. Ondansetron was injected through intrathecal catheterization. Results: The results demonstrated that Tph, the rate-limiting enzyme in 5-HT synthesis, was significantly upregulated in the RVM, and that spinal 5-HT release was increased in CIPN rats. Intra-RVM microinjection of Tph inhibitor PCPA significantly attenuated mechanical and thermal pain behavior through Tph downregulation and decreased spinal 5-HT. Intra-RVM administration of p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 alleviated paclitaxel-induced pain in a similar manner to PCPA. Intrathecal injection of ondansetron, a 5-HT3 receptor antagonist, partially reversed paclitaxel-induced pain, indicating that 5-HT3 receptors were involved in descending serotoninergic modulation of spinal pain processing. Conclusion: The results suggest that activation of the p38 MAPK pathway in the RVM leads to increased RVM Tph expression and descending serotoninergic projection to the spinal dorsal horn and contributes to the persistence of CIPN via spinal 5-HT3 receptors.

Bulbospinal nociceptive ON and OFF cells related neural circuits and transmitters

“…In neuropathic or inflammatory pain states, blocking the 5-HT3R specifically attenuates 5-HT pronociceptive actions in the RVM while activation of the 5-HT3R plays a facilitatory role in nociceptive responses. These findings were in parallel with the observations that a descending release of 5-HT from the RVM combined with the upregulation of 5-HT3R expression in spinal cord neurons was detected after inflammation and nerve injury ( Wei et al, 2010 ; Wang et al, 2019 ; Liu et al, 2020 ). Thus, it is confirmed that spinal 5-HT3R mainly mediates descending facilitation under abnormal pain conditions.…”

“…Thus, it is confirmed that spinal 5-HT3R mainly mediates descending facilitation under abnormal pain conditions. Specifically, activation of the p38 mitogen-induced protein kinase (p38MAPK) pathway in the RVM increases the expression of tryptophan hydroxylase (Tph), resulting in increased activities of ON cells and expression of 5-HT along with the silencing of OFF cells, which then act on the spinal 5-HT3R to activate ATP-gated P2X7 receptors in the microglia, and ultimately exerting pain hypersensitivity ( Liu et al, 2020 ). As 5-HT3R is also expressed on inhibitory GABAergic interneurons, antinociceptive effects are confirmed to correspond to activation of OFF cells in subcutaneously excited RVM 5-HT3R and GABA release in the GABA spinal cord in acute pain models ( Nasirinezhad et al, 2016 ; Kort et al, 2022 ).…”

Preclinical research in paclitaxel-induced neuropathic pain: a systematic review

“…Emerging mechanism in neuroscience research were evaluated namely in what concerns the gut-brain axis (78,91) or circadian regulation (53).…”

JAG-1/Notch signaling axis contributes to the maintenance of bone cancer pain in female rats via spinal astrocyte-neuron crosstalk

“…Intrathecal catheterization was performed as described previously [16,17]. Brie y, rats were anesthetized, a longitudinal 1.5 cm incision was made in the skin at the level of L4-L5, and the sphenoid of L4 was excised until the spinal dura was exposed.…”