Nicotine withdrawal induces hyperalgesia via downregulation of descending serotonergic pathway in the nucleus raphe magnus

Shen, Ling; Qiu, Haibo; Xu, Huihong; Wei, Kai; Zhao, Liang; Zhu, Chengcheng; Li, Cheng-Jian; Lu, Zhijie

doi:10.1016/j.neuropharm.2021.108515

Cited by 6 publications

(6 citation statements)

References 36 publications

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“…6 L 1 , M) engaged in nociception/pain regulation. The NRM receives inputs from the PAG (see below) and mainly projects to the spinal cord DH [ 50 ]. In the SCI tissue sections, significantly increased group average IRL of GFAP was observed in NRM, compared to the control group (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…7 A) that disseminate sensory information (e.g., temperature, pain, etc.) to forebrain structures (e.g., the thalamus, hypothalamus, and extended amygdala) with the involvement of their CGRP+ neurons in the development of NP [ 50 – 52 ]. SCI LPBN displayed significantly elevated group mean IRL of co-stained Iba-1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The results collectively suggested that the DH neural network under this scale of hypersensitivity was still in a state attempting to modulate the elevated nociceptive input via enhancement of Homer-1a and 5HT expression. Since treating rats 3 weeks after the same type of SCI with huperzine A, a multimodal neuromodulation drug, markedly impeded NIF, DH expression of Homer-1a, and NP-like behaviors [ 14 ], future therapeutic development should target these neurodynamic events to manage SCI NP [ 50 , 91 – 93 ].…”

Section: Discussionmentioning

confidence: 99%

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Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: a systematic approach to profiling neuropathic pain

Wang

Gunduz

Semeano

et al. 2022

J Neuroinflammation

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Background People with spinal cord injury (SCI) frequently develop neuropathic pain (NP) that worsens disability and diminishes rehabilitation efficacy. Chronic NP is presently incurable due to poor understanding of underlying mechanisms. We hypothesized that multilocus neuroinflammation (NIF) might be a driver of SCI NP, and tested it by investigating whether NP coexisted with central NIF, neurotransmission (NTM), neuromodulation (NML) and neuroplasticity (NPL) changes post-SCI. Methods Female Sprague–Dawley rats (230–250 g) with T10 compression or laminectomy were evaluated for physical conditions, coordinated hindlimb functions, neurological reflexes, and mechanical/thermal sensitivity thresholds at 1 day post-injury (p.i.) and weekly thereafter. Eight weeks p.i., central nervous system tissues were histochemically and immunohistochemically characterized for parameters/markers of histopathology and NIF/NTM/NML/NPL. Also analyzed was the correlative relationship between levels of selected biomarkers and thermosensitivity thresholds via statistical linear regression. Results SCI impaired sensorimotor functions, altered reflexes, and produced spontaneous pain signs and hypersensitivity to evoked nociceptive, mechanical, and thermal inputs. Only injured spinal cords exhibited neural lesion, microglia/astrocyte activation, and abnormal expression of proinflammatory cytokines, as well as NIF/NTM/NML/NPL markers. Brains of SCI animals displayed similar pathophysiological signs in the gracile and parabrachial nuclei (GrN and PBN: sensory relay), raphe magnus nucleus and periaqueduct gray (RMN and PAG: pain modulation), basolateral amygdala (BLA: emotional-affective dimension of pain), and hippocampus (HPC: memory/mood/neurogenesis). SCI augmented sensory NTM/NPL (GrN and PBN); increased GAD67 (PAG) level; reduced serotonin (RMN) and fear-off neuronal NTR2 (BLA) expressions; and perturbed neurogenesis (HPC). Conclusion T10 compression caused chronic hyperalgesia that coexisted with NIF/NTM/NML/NPL responses at multilevel neuroaxis centers. The data have provided multidimensional biomarkers as new mechanistic leads to profile SCI NP for therapeutic/therapy development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: a systematic approach to profiling neuropathic pain

Wang

Gunduz

Semeano

et al. 2022

J Neuroinflammation

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“…As for the neurobiological mechanism of nicotine withdrawal-induced hyperalgesia, nicotine withdrawal reportedly causes a sudden increase in unbound nAChR ligands, which decreases the central release of opioids, norepinephrine and serotonin [13]. The decrease in these neurotransmitters further leads to descending pain modulation system dysfunction, which contributes to the adverse effects of analgesics in smokers [14]. Therefore, NRT should be an important part of both the perioperative smoking cessation plan and postoperative multimodal analgesia for abstinent smokers.…”

Section: Discussionmentioning

confidence: 99%

Effect of perioperative high‐dose transdermal nicotine patch on pain sensitivity among male abstinent tobacco smokers undergoing abdominal surgery: A randomized controlled pilot study

Zhu

Wei

et al. 2023

Addiction

Self Cite

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Background and Aims Previous studies have focused on the role of perioperative nicotine replacement therapy (NRT) in improving the success rate of long‐term smoking cessation in tobacco smokers. This study aimed to measure the effectiveness of high‐dose NRT in alleviating postoperative pain for male abstinent smokers receiving abdominal surgery. Design This was a parallel‐group, randomized, double‐blind and controlled pilot trial. Setting and participants In total, 101 male smoking‐abstinent patients from the Eastern Hepatobiliary Surgery Hospital, Shanghai, China, from 8 October 2018 to 10 December 2021. Interventions Patients started smoking cessation on admission to the hospital ward. Patients received 24‐hour transdermal nicotine patches (n = 50) or placebo (n = 51) every day from admission until 48 hours after surgery. Measurements The primary outcomes were pre‐surgery pain thresholds and total consumption of analgesics within the first 48 hours after surgery. Secondary outcomes included postoperative pain and sedation scores, nausea, vomiting and fever frequency within the treatment period. Findings Both pre‐surgery electrical and mechanical pain thresholds in the NRT group were higher than those in the placebo group (P = 0.004 and P = 0.020, respectively). The 48‐hour postoperative analgesic consumption was significantly lower for smoking‐abstinent patients receiving NRT than those receiving placebo (standardized morphine equivalent requirement, median [interquartile range], 1.80 [1.47, 2.32] mg/kg vs 2.22 [1.62, 2.82] mg/kg, P = 0.011). Postoperative pain intensity was significantly lower in the NRT group than that in the placebo group at 1st hour and 24th hour post‐surgery (P < 0.001 and P = 0.012, respectively). The incidence of treatment‐related adverse events was not significantly different between groups. Conclusions Perioperative high‐dose nicotine replacement therapy may help to relieve postoperative pain among male smoking‐abstinent patients undergoing abdominal surgery.

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“…During the elimination of neuroin ammation, astrocytes inhibited neuroin ammation by down-regulating the expression of in ammatory factors through the Gi pathway in GPCR [40]. TPH1 (Tryptophan hydroxylase 1) worked as a rate-limiting enzyme in the biosynthesis of 5-Hydroxytryptamine (5-HT), and the reduction of which in cerebrospinal uid would led to mechanical hyperalgesia with central sensitization [41,42]. Whereas the TPH1 overexpression promoted the synthesis of 5-methoxytryptophan (5-MTP), improved nephritis and renal brosis [43].…”

Section: Discussionmentioning

confidence: 99%

Anemoside B4 alleviates neuropathic pain through inhibiting inflammation

Zhao,

Li,

Yang

et al. 2022

Preprint

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Research background: Neuropathic pain (NP), which is caused by nerve injury or other diseases damages patients’ life quality seriously. Anemoside B4 (AB4) is the active component of triterpenoid saponins in traditional Chinese medicine Pulsatilla, with prominent effects of anti-inflammation and analgesia. However, its pharmacological mechanisms acting on NP remains unclear.Methods: The analgesia effects of AB4 against NP were investigated on the basis of the spinal nerve ligation (SNL) rat model by detecting the thresholds of mechanical pain and response times to cold stimulate. The key targets of AB4 acting on NP is selected based on the transcriptomic analysis, and their relative expression level was further verified by RT-qPCR. The binding sites of AB4 to the targets were searched by molecular docking. The regulation effects of AB4 on cytokines including IL-1β, IL-6 and TNF-α in the serum of SNL rats were tested by ELISA.Results: In contrast with normal rats, the thresholds of mechanical pain was decreased, whereas the response times to cold stimulate was increased in SNL rats, and the above phenomenon was reversed by AB4 treatment. The transcriptome sequencing results revealed that AB4 mainly regulated the serotonergic synapse, glutamatergic synapse, GABAergic synapse, dopaminergic synapse and cholinergic synapse pathways which was closely related to neuroinflammation and central pain sensitization. Further overlap analysis selected five genes in the pathway, named Alox15, Gngt1, Gngt2, Gnb3 and Tph1 respectively. Further RT-qPCR confirmed that the gene expression of them was down-regulated in the hippocampus of SNL rats, and up-regulated by AB4 administration. According to the molecular docking results, Anemoside B4 forms tightly bonded hydrogen bonding forces with key target molecules of the synaptic pathway, including Alox15, Gngt1, Gngt2, Gnb3 and Tph1. In addition, AB4 treatment also decreased the contents of inflammatory cytokines IL-1β, IL-6 and TNF-α in the serum of SNL rats.Conclusion: Our findings suggested the possibility of AB4 as a promising candidate for NP treatment by inhibiting inflammation.

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Nicotine withdrawal induces hyperalgesia via downregulation of descending serotonergic pathway in the nucleus raphe magnus

Cited by 6 publications

References 36 publications

Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: a systematic approach to profiling neuropathic pain

Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: a systematic approach to profiling neuropathic pain

Effect of perioperative high‐dose transdermal nicotine patch on pain sensitivity among male abstinent tobacco smokers undergoing abdominal surgery: A randomized controlled pilot study

Anemoside B4 alleviates neuropathic pain through inhibiting inflammation

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