Lactate Concentrations in Incisions Indicate Ischemic-like Conditions May Contribute to Postoperative Pain

Kim, Tae Jung; Freml, Luke; Park, Soo Seog; Brennan, Timothy J.

doi:10.1016/j.jpain.2006.06.003

Cited by 70 publications

(67 citation statements)

References 32 publications

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“…A greater response to pH 6.0 and lactic acid of the afferent fibers innervating the rat hindpaw skin has been described after incision (Kang and Brennan, 2009). Lactate enhances the activity of ASIC3 (Immke and McCleskey, 2001), and the increase in tissue lactate concentration (and possibly other mediators) that parallels the decrease in tissue pH after incision may potentiate the acid-induced activity of ASIC3 (Woo et al, 2004;Kim et al, 2007). This effect can be reinforced by the increased expression of ASIC3 in nociceptors 24 h after incision that was observed in the present work.…”

Section: Discussionsupporting

confidence: 71%

Acid-Sensing Ion Channels in Postoperative Pain

Deval¹,

Noël²,

Gasull³

et al. 2011

J. Neurosci.

154

148

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Iatrogenic pain consecutive to a large number of surgical procedures has become a growing health concern. The etiology and pathophysiology of postoperative pain are still poorly understood, but hydrogen ions appear to be important in this process. We have investigated the role of peripheral acid-sensing ion channels (ASICs), which form depolarizing channels activated by extracellular protons, in a rat model of postoperative pain (i.e., hindpaw skin/muscle incision). We report high levels of ASIC-type currents (ϳ77%) in sensory neurons innervating the hindpaw muscles, with a prevalence of ASIC3-like currents. The ASIC3 protein is largely expressed in lumbar DRG neurons innervating the plantar muscle, and its mRNA and protein levels are increased by plantar incision 24 h after surgery. Pharmacological inhibition of ASIC3 channels with the specific toxin APETx2 or in vivo knockdown of ASIC3 subunit by small interfering RNA led to a significant reduction of postoperative spontaneous, thermal, and postural pain behaviors (spontaneous flinching, heat hyperalgesia, and weight bearing). ASIC3 appears to have an important role in deep tissue but also affects prolonged pain evoked by skin incision alone. The specific homomeric ASIC1a blocker PcTx1 has no effect on spontaneous flinching, when applied peripherally. Together, these data demonstrate a significant role for peripheral ASIC3-containing channels in postoperative pain.

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Section: Discussionsupporting

confidence: 71%

Acid-Sensing Ion Channels in Postoperative Pain

Deval¹,

Noël²,

Gasull³

et al. 2011

J. Neurosci.

154

148

View full text Add to dashboard Cite

show abstract

“…As expected, the lactate production was substantially augmented in the DRGs of diabetic animals compared with that of control animals. In this study, DRG lactate concentration in control animals has been found to be 0.74 mmol/liter, which is consistent with the previous study showing a lactate level of less than 2 mmol/liter in normal hind paw tissue (53). Pdk2/4 deficiency lessened the hyperglycemia-induced lactate surge (Fig.…”

Section: Enhanced Expression and Activity Of Pdk2 And Pdk4 In Thesupporting

confidence: 92%

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

Rahman

Jha

Kim

et al. 2016

Journal of Biological Chemistry

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The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy.Painful neuropathy is one of the most common complications of diabetes. Patients with diabetes frequently exhibit a variety of aberrant sensations, including pain hypersensitivity (1, 2). Interrelation and mutual perpetuation of distinct aberrations of specific metabolic pathways cause painful diabetic neuropathy. Furthermore, painful diabetic neuropathy probably results from a combination of metabolic and immune factors (3, 4). Metabolic aberrations are thought to be early events in painful diabetic neuropathy, leading to biochemical, structural, and functional changes in the dorsal root ganglion (DRG) 3 and its nerve trunk (5, 6). Likewise, hyperglycemia-induced immune activation creates an inflammatory microenvironment surrounding the influenced nerves (7).The DRG is pathologically important in diabetes presenting with painful neuropathic states, which patients with early polyneuropathy commonly experience (8). Ganglionic sensory neurons are devoid of any special protection by the blood-brain or blood-nerve barrier and have higher metabolic requirements than the nerve trunk, which makes the ganglion a vulnerable site in the pathogenesis of diabetic neurop...

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“…Lactate may assist in the detection of exercise stress before tissue damage occurs and can be exchanged rapidly among tissue compartments where it may be oxidized as a fuel or reconverted to form pyruvate or glucose (Gladden, 2004;Kim et al, 2007;Philip et al, 2005;Robergs et al, 2004). Lactate is also involved in peripheral nociception and it appears to facilitate the response of the acid-sensing ion channel 3 (ASIC-3) to low pH (Kim et al, 2007).…”

Section: Metabolitesmentioning

confidence: 99%

“…Lactate is also involved in peripheral nociception and it appears to facilitate the response of the acid-sensing ion channel 3 (ASIC-3) to low pH (Kim et al, 2007). Such ASIC channels are considered to be molecular transducers for nociception and mechanosensation (Kim et al, 2007).…”

Section: Metabolitesmentioning

confidence: 99%