Neuroimmune-Driven Neuropathic Pain Establishment: A Focus on Gender Differences

Coraggio, Vincenzo; Guida, Francesca; Boccella, Serena; Scafuro, Marika; Paino, Salvatore; Romano, Domenico; Maione, Sabatino; Luongo, Livio

doi:10.3390/ijms19010281

Cited by 49 publications

(36 citation statements)

References 85 publications

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“…In fact, whereas the effective dose of DMF was 150 mg/kg in male mice, a half dose (75 mg/kg) significantly reduced tactile allodynia in female mice. This finding was not surprising because clinical (31,32) and preclinical (33)(34)(35)(36) evidence strongly supports that sex differences are known to exist in neuropathic pain disorders. In particular, the involvement of both innate and adaptive immunity in neuropathic pain pathophysiology has been indicated based on the identification of different immune cell-driven allodynia induction in male and female mice (36).…”

Section: Discussionmentioning

confidence: 70%

Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain

et al. 2018

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The mechanisms underlying neuropathic pain are poorly understood. Here we show the unexplored role of the hydroxyl carboxylic acid receptor type 2 (HCAR2) in 2 models of neuropathic pain. We used an oral treatment with dimethyl fumarate and the HCAR2 endogenous ligand β-hydroxybutyrate (BHB) in wild-type (WT) and HCAR2-null mice. We found an up-regulation of the HCAR2 in the sciatic nerve and the dorsal root ganglia in neuropathic mice. Accordingly, acute and chronic treatment with dimethylfumarate (DMF) and BHB reduced the tactile allodynia. This effect was completely lost in the HCAR2-null mice after a 2-d starvation protocol, in which the BHB reached the concentration able to activate the HCAR2-reduced tactile allodynia in female WT mice, but not in the HCAR2-null mice. Finally, we showed that chronic treatment with DMF reduced the firing of the ON cells (cells responding with an excitation after noxious stimulation) of the rostral ventromedial medulla. Our results pave the way for investigating the mechanisms by which HCAR2 regulates neuropathic pain plasticity.-Boccella, S., Guida, F., De Logu, F., De Gregorio, D., Mazzitelli, M., Belardo, C., Iannotta, M., Serra, N., Nassini, R., de Novellis, V., Geppetti, P., Maione, S., Luongo, L. Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain.

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Section: Discussionmentioning

confidence: 70%

Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain

et al. 2018

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“…Along this line, increasing evidence suggests that pain-associated neuroinflammation is gender-dependent, with a greater involvement of microglia in males and T lymphocytes in females (reviewed by Coraggio et al. 47 ). Sex steroids are known to affect neuroinflammation by modulating microglial responses to injuries.…”

Section: Discussionmentioning

confidence: 99%

Multimodal antidepressant vortioxetine causes analgesia in a mouse model of chronic neuropathic pain

et al. 2018

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Vortioxetine is a multimodal antidepressant that potently antagonizes 5-HT3 serotonin receptors, inhibits the high-affinity serotonin transporter, activates 5-HT1A and 5-HT1B receptors, and antagonizes 5-HT1D and 5-HT7 receptors. 5-HT3 receptors largely mediate the hyperalgesic activity of serotonin that occurs in response to nerve injury. Activation of 5-HT3 receptors contributes to explain why selective serotonin reuptake inhibitors, such as fluoxetine, are not indicated in the treatment of neuropathic pain. Here, we studied the analgesic action of vortioxetine in the chronic constriction injury model of neuropathic pain in mice. Vortioxetine was injected once a day for 27 days at doses (10 mg/kg, intraperitoneally) that determine >90% 5-HT3 receptor occupancy in the central nervous system. The action of vortioxetine was compared to the action of equal doses of the serotonin-noradrenaline reuptake inhibitor, venlafaxine (one of the gold standard drugs in the treatment of neuropathic pain), and fluoxetine. Vortioxetine caused a robust analgesia in chronic constriction injury mice, and its effect was identical to that produced by venlafaxine. In contrast, fluoxetine was inactive in chronic constriction injury mice. Vortioxetine enhanced mechanical pain thresholds in chronic constriction injury mice without changing motor activity, as assessed by the open-field and horizontal bar tests. None of the three antidepressants caused analgesia in the complete Freund’s adjuvant model of chronic inflammatory pain. These findings raise the attractive possibility that vortioxetine can be effective in the treatment of neuropathic pain, particularly in patients with comorbid depression and cognitive dysfunction.

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“…Neuropathic pain is an abnormal perception of pain [20] that affects 7-10% percent of the human population worldwide [19]. Neuropathic pain can cause increased pain sensitivity to mechanical or thermal stimuli [20].…”

Section: Introductionmentioning

confidence: 99%

A network approach to investigating the key microbes and stability of gut microbial communities in a mouse neuropathic pain model

et al. 2020

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Background Neuropathic pain is an abnormally increased sensitivity to pain, especially from mechanical or thermal stimuli. To date, the current pharmacological treatments for neuropathic pain are still unsatisfactory. The gut microbiota reportedly plays important roles in inducing neuropathic pain, so probiotics have also been used to treat it. However, the underlying questions around the interactions in and stability of the gut microbiota in a spared nerve injury-induced neuropathic pain model and the key microbes (i.e., the microbes that play critical roles) involved have not been answered. We collected 66 fecal samples over 2 weeks (three mice and 11 time points in spared nerve injury-induced neuropathic pain and Sham groups). The 16S rRNA gene was polymerase chain reaction amplified, sequenced on a MiSeq platform, and analyzed using a MOTHUR- UPARSE pipeline. Results Here we show that spared nerve injury-induced neuropathic pain alters gut microbial diversity in mice. We successfully constructed reliable microbial interaction networks using the Metagenomic Microbial Interaction Simulator (MetaMIS) and analyzed these networks based on 177,147 simulations. Interestingly, at a higher resolution, our results showed that spared nerve injury-induced neuropathic pain altered both the stability of the microbial community and the key microbes in a gut micro-ecosystem. Oscillospira, which was classified as a low-abundance and core microbe, was identified as the key microbe in the Sham group, whereas Staphylococcus, classified as a rare and non-core microbe, was identified as the key microbe in the spared nerve injury-induced neuropathic pain group. Conclusions In summary, our results provide novel experimental evidence that spared nerve injury-induced neuropathic pain reshapes gut microbial diversity, and alters the stability and key microbes in the gut.

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Neuroimmune-Driven Neuropathic Pain Establishment: A Focus on Gender Differences

Cited by 49 publications

References 85 publications

Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain

Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain

Multimodal antidepressant vortioxetine causes analgesia in a mouse model of chronic neuropathic pain

A network approach to investigating the key microbes and stability of gut microbial communities in a mouse neuropathic pain model

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