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The Contribution of Nitroxidative Stress to Pathophysiological Pain and Opioid Analgesic Failure

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Redox-Active Therapeutics

Abstract

Chronic pain affects nearly 10 % of the population worldwide and poses a tremendous socioeconomic burden. Current therapeutic strategies, which range from nonsteroidal anti-inflammatory drugs (NSAIDs) to powerful opioids like morphine and fentanyl, do not effectively manage chronic pain in the majority of patients. A better understanding of pathophysiological nociception and the therapeutic targets therein is necessary. The generation of nitroxidative (nitrative and oxidative) stress—that is, the formation of superoxide and nitric oxide in tandem, their subsequent reaction to afford peroxynitrite, and the reaction of peroxynitrite and its decomposition products with biological molecules—is clearly involved in various types of persistent pain. In this chapter, we will catalogue the mechanistic pharmacological studies that support the contribution of nitroxidative stress to chronic pain, identify the cellular and enzymatic sources of nitroxidative species involved in this pathology, and delineate the mechanisms by which nitroxidative stress impacts nociceptive processing to produce persistent pain. Specifically, we will highlight the contribution of peroxynitrite (e.g., through nitration chemistry) to enhanced pro-nociceptive neurotransmission (modifications of glutamatergic, vanilloid, and prostaglandin signaling), suppressed inhibitory neurotransmission (modifications of GABAergic and catecholamine signaling), and to changes in transcriptional regulation that underpin chronic pain. Our overall goal is to refine the current generalized understanding of roles of reactive oxygen and nitrogen species in persistent pain by defining nitroxidative stress as a specific, targetable pro-nociceptive mechanism for the ultimate treatment of chronic pain.

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Abbreviations

COX:

Cyclooxygenase

DA:

Dopamine

EAAC1:

Excitatory amino acid carrier 1

GABA:

Gamma aminobutyric acid

GLAST/EAAT1:

Glutamate aspartate transporter/excitatory amino acid transporter 1

GLT-1/EAAT2:

Glutamate transporter 1/excitatory amino acid transporter 2

GS:

Glutamine synthase

HDAC:

Histone deacetylase

MENK:

Met-enkephalin

NaV:

Voltage-gated sodium channel

NE:

Norepinephrine

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOX:

NADPH oxidase

NSAID:

Nonsteroidal anti-inflammatory drug

PAG:

Periaqueductal grey

PN:

Peroxynitrite

PNDC:

Peroxynitrite decomposition catalyst

PNI:

Peripheral nerve injury

PTM:

Post-translational modification

RVM:

Rostral ventromedial medulla

SC:

Spinal cord

PK:

Protein kinase

SO:

Superoxide

SOD:

Superoxide dismutase

SODm:

Superoxide dismutase mimetic

TH:

Tyrosine hydroxylase

TRP:

Transient receptor potential

XO:

Xanthine oxidase

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Acknowledgment

We would like to acknowledge our funding support from NIH/NIDA RO1 DA024074 and the NIH/NCI RO1 CA169519.

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Authors and Affiliations

  1. Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO, 63104, USA

    Ashley M. Symons-Liguori, Kali Janes & Daniela Salvemini

  2. Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 200 University Park, Edwardsville, IL, 62026, USA

    William L. Neumann

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  1. Ashley M. Symons-Liguori
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  2. Kali Janes
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  4. Daniela Salvemini
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Correspondence to Ashley M. Symons-Liguori or Daniela Salvemini .

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  1. Duke University School of Medicine, Durham, North Carolina, USA

    Ines Batinić-Haberle

  2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

    Júlio S. Rebouças

  3. Duke University School of Medicine, Durham, North Carolina, USA

    Ivan Spasojević

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Symons-Liguori, A.M., Janes, K., Neumann, W.L., Salvemini, D. (2016). The Contribution of Nitroxidative Stress to Pathophysiological Pain and Opioid Analgesic Failure. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_25

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