Nitroxidative stress in pain and opioid-induced adverse effects: therapeutic opportunities

Squillace, Silvia; Salvemini, Daniela

doi:10.1097/j.pain.0000000000002347

Cited by 8 publications

(6 citation statements)

References 182 publications

(242 reference statements)

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“…Neuroinflammation involves glial cells (microglia and astrocyte) activation, chemokines (CCL1, CCL2, CCL7, CXCL1) release and pro-inflammatory mediators (TNF-α, IL-1β, IL-18, BDNF, PGE2) secretion in pain neural circuitry that, subsequently, mediates excitatory neuronal plasticity and synaptic transmission for producing and sustaining chronic inflammatory pain, chronic neuropathic pain, chronic fracture-associated pain, as well as chronic cancer pain ( Zhang et al, 2013 ; Ji et al, 2014 ; Ni et al, 2019 ; Qiang and Yu, 2019 ; Wang et al, 2020b ). Accumulating evidence emphasizes that oxidative stress drive neuronal apoptosis and sensitize nociceptors in the pathogenesis of chronic pain, such as chemotherapy-induced peripheral neuropathy (CIPN) and opioid-induced hyperalgesia (OIH) ( Zhang et al, 2014 ; Shu et al, 2015 ; Grace et al, 2016a ; Yousuf et al, 2020 ; Squillace and Salvemini, 2022 ). Nevertheless, the involvement of specific molecular signaling in neuroinflammation and neuronal apoptosis remains controversial.…”

Section: Introductionmentioning

confidence: 99%

The Involvement of Caspases in Neuroinflammation and Neuronal Apoptosis in Chronic Pain and Potential Therapeutic Targets

Zhang

et al. 2022

Front. Pharmacol.

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Chronic pain is a common, complex and unpleasant sensation following nerve injury, tissue trauma, inflammatory diseases, infection and cancer. It affects up to 25% of adults and is increasingly recognized as the leading cause of distress, disability and disease burden globally. Chronic pain is often refractory to most current analgesics, thus emphasizing the requirement for improved therapeutic medications. It is of great importance to elucidate the specific pathogenesis of chronic pain with different etiologies. Recent progress has advanced our understanding in the contribution of neuroinflammation and glial cells (microglia and astrocyte) activation in the plasticity of excitatory nociceptive synapses and the development of chronic pain phenotypes. Oxidative stress-associated neuronal apoptosis is also identified to be a pivotal step for central pain sensitization. The family of cysteine aspartate specific proteases (Caspases) has been well known to be key signaling molecules for inflammation and apoptosis in several neurological conditions. Recent studies have highlighted the unconventional and emerging role of caspases in microgliosis, astrocytes morphogenesis, chemokines release, cytokines secretion and neuronal apoptosis in initiating and maintaining synaptogenesis, synaptic strength and signal transduction in persistent pain hypersensitivity, suggesting the possibility of targeting caspases pathway for prevention and treatment of chronic pain. In this review, we will discuss and summarize the advances in the distinctive properties of caspases family in the pathophysiology of chronic pain, especially in neuropathic pain, inflammatory pain, cancer pain and musculoskeletal pain, with the aim to find the promising therapeutic candidates for the resolution of chronic pain to better manage patients undergoing chronic pain in clinics.

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Section: Introductionmentioning

confidence: 99%

The Involvement of Caspases in Neuroinflammation and Neuronal Apoptosis in Chronic Pain and Potential Therapeutic Targets

Zhang

et al. 2022

Front. Pharmacol.

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“…We previously reported that direct S1PR1 activation in the CNS with highly selective S1PR1 agonists forms peroxynitrite (18), a powerful nitrating agent, and activates the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome (19). Peroxynitrite nitrates mitochondrial manganese superoxide dismutase (MnSOD) at Tyr-34 via an Mn-catalyzed process that inactivates the enzyme by more than 80% and results in mitochondrial dysfunction (20,21). In contrast, NLRP3 is critical for formation of interleukin 1β (IL-1β) and IL-18, inflammatory cytokines with known roles in cognitive impairment (22,23).…”

Section: Resultsmentioning

confidence: 99%

Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment

Squillace¹,

Niehoff²,

Doyle³

et al. 2022

Journal of Clinical Investigation

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“…An additional value of the boronate-based agents is their ability to scavenge ONOO – and prevent ONOO – -dependent oxidation and nitration processes. The potential synergy between scavenging ONOO – by AMBB, and the analgesic activity of the reaction product, AM, is an exciting avenue to explore for the treatment of neuropathic pain. − …”

Section: Discussionmentioning

confidence: 99%

“…The potential synergy between scavenging ONOO – by AMBB, and the analgesic activity of the reaction product, AM, is an exciting avenue to explore for the treatment of neuropathic pain. 46 − 49 …”

Section: Discussionmentioning

confidence: 99%

Boronate-Based Oxidant-Responsive Derivatives of Acetaminophen as Proinhibitors of Myeloperoxidase

Pierzchała

Pięta

et al. 2023

Chem. Res. Toxicol.

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Myeloperoxidase (MPO) is an important component of the human innate immune system and the main source of a strong oxidizing and chlorinating species, hypochlorous acid (HOCl). Inadvertent, misplaced, or excessive generation of HOCl by MPO is associated with multiple human inflammatory diseases. Therefore, there is a considerable interest in the development of MPO inhibitors. Here, we report the synthesis and characterization of a boronobenzyl derivative of acetaminophen (AMBB), which can function as a proinhibitor of MPO and release acetaminophen, the inhibitor of chlorination cycle of MPO, in the presence of inflammatory oxidants, i.e., hydrogen peroxide, hypochlorous acid, or peroxynitrite. We demonstrate that the AMBB proinhibitor undergoes conversion to acetaminophen by all three oxidants, with the involvement of the primary phenolic product intermediate, with relatively long half-life at pH 7.4. The determined rate constants of the reaction of the AMBB proinhibitor with hydrogen peroxide, hypochlorous acid, or peroxynitrite are equal to 1.67, 1.6 × 104, and 1.0 × 106 M–1 s–1, respectively. AMBB showed lower MPO inhibitory activity (IC50 > 0.3 mM) than acetaminophen (IC50 = 0.14 mM) toward MPO-dependent HOCl generation. Finally, based on the determined reaction kinetics and the observed inhibitory effects of two plasma components, uric acid and albumin, on the extent of AMBB oxidation by ONOO– and HOCl, we conclude that ONOO– is the most likely potential activator of AMBB in human plasma.

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Nitroxidative stress in pain and opioid-induced adverse effects: therapeutic opportunities

Cited by 8 publications

References 182 publications

The Involvement of Caspases in Neuroinflammation and Neuronal Apoptosis in Chronic Pain and Potential Therapeutic Targets

The Involvement of Caspases in Neuroinflammation and Neuronal Apoptosis in Chronic Pain and Potential Therapeutic Targets

Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment

Boronate-Based Oxidant-Responsive Derivatives of Acetaminophen as Proinhibitors of Myeloperoxidase

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