Tumour necrosis factor-α induces ectopic activity in nociceptive primary afferent fibres

Sorkin, Linda S.; Xiao, Wen; Wagner, Rochelle; Myers, Robert R.

doi:10.1016/s0306-4522(97)00147-4

Cited by 477 publications

(252 citation statements)

References 29 publications

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“…A direct excitatory action of the proinflammatory cytokines therefore was not expected, and none of the compounds induced CGRP release directly in the present in vitro study. Ectopic excitatory activity that was observed when TNF-␣ was applied in anesthetized animals thus seem to be attributable to indirect cytokine effects on nociceptors (Sorkin et al, 1997). However, on the basis of several findings, sensitization of nociceptors could be expected to occur during the time course of inflammation, which can be explained by activation of kinases in the signaling pathway of the cytokines investigated in the present study.…”

Section: Discussionmentioning

confidence: 51%

“…Second, some cytokines such as TNF-␣ or IL-1␤ have been used for adjuvant chemotherapy, but approximately one-half of the treated patients developed pain syndromes and complained about local tenderness at the injection site (Kemeny et al, 1990;Del Mastro et al, 1995;Elkordy et al, 1997). In experimental models, TNF-␣ and IL-1␤ induced excitation in nociceptors and hyperalgesia (Ferreira et al, 1988;Cunha et al, 1992;Sorkin et al, 1997;Kanaan et al, 1998;Sommer et al, 1998Sommer et al, , 1999, and both are suggested to activate receptor-associated kinases, e.g., IL-1 receptor-associated kinase (IRAK) (Cao et al, 1996). Such kinases may phosphorylate ion channels transducing noxious heat in nociceptors, e.g., VR-1.…”

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confidence: 99%

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Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

2000

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Proinflammatory cytokines contribute to the development of inflammatory and neuropathic pain and hyperalgesia in many in vivo models. The rat skin model was used to investigate the effects of proinflammatory cytokines on the basal and heatevoked release of calcitonin gene-related peptide from nociceptors in vitro. In contrast to the excitatory effects of cytokines observed in vivo, none of the cytokines tested evoked any calcitonin gene-related peptide (CGRP) release at normal skin temperature of 32°C. However, the cytokines IL-1␤, tumor necrosis factor (TNF)-␣, and IL-6 but not IL-8 induced a pronounced and transient sensitization of the heat-evoked CGRP release from nociceptors in vitro. This heat sensitization was dose dependent, with EC 50 for IL-1␤ of 2.7 ng/ml and for TNF-␣ of 3.1 ng/ml. The maximum IL-1␤ effect reached almost 600% of the heat-evoked release, and the maximum TNF-␣ effect induced a rise in CGRP release of 350%. In contrast to IL-1␤ and TNF-␣, IL-6 did not induce heat sensitization when applied alone but was only effective in the presence of soluble IL-6 receptor. This suggests a constitutive expression of signaling receptors for TNF and IL-1␤ and the signal transduction molecule gp130 but not IL-6 receptor or IL-8 receptor. Furthermore, the acute cytokine signaling observed in the present study was independent of transcriptional pathways because sensitization occurred on short latency in vitro and under conditions that excluded chemotactic accumulation of immune cells from blood vessels. Our results demonstrate that interleukins may play an important role in the initiation of heat hyperalgesia in inflammation and neuropathy.

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Section: Discussionmentioning

confidence: 51%

mentioning

confidence: 99%

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

2000

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“…2,8,11,30 Changes in these substances could directly activate nociceptors through acid sensing ion channels and increased release of cytokines and prostaglandins. 5,22,27,31,42,43,47 Alternatively, there could be changes in the buffering capacity of the muscle to maintain pH such that a pH of 5 is buffered slower than under nonfatigue conditions. 13,33 However, the current study was unable to detect changes in lactate, phosphate, creatinine kinase, or to detect infiltration of neutrophils in the muscle, suggesting that metabolic changes in the muscle associated with damage are unlikely to contribute to the enhanced nociceptive response to pH.…”

Section: Peripheral Mechanisms For Enhanced Nociception After Fatiguementioning

confidence: 99%

Muscle Fatigue Increases the Probability of Developing Hyperalgesia in Mice

Yokoyama

Lisi

Moore

et al. 2007

The Journal of Pain

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Chronic muscle pain is a major clinical problem that is often associated with fatigue. Conversely, chronic fatigue conditions are commonly associated with muscle pain. We tested the hypothesis that muscle fatigue enhances hyperalgesia associated with injection of acidic saline into muscle. We evaluated mechanical sensitivity of the paw (von Frey) in mice after 2 intramuscular injections of saline (20 µL; pH 4, pH 5, pH 6, pH 7.2) in a fatigue and a control group. To induce fatigue, mice were run for 2 h/day for 2 days prior to the first injection and 2 h/day for 2 days prior to the second injection. Muscle lactate, pCO 2 , pO 2 , creatinine kinase, phosphate, and histology were examined after the fatigue task and compared to a control group. Grip force was significantly decreased after 2 h of running indicating fatigue. The fatigue task did not induce muscle damage as there was no difference in muscle lactate, pCO 2 , pO 2 , creatinine kinase, phosphate, or histology. The fatigue task altered the dose-response relationship to intramuscular acidic saline injections. Mechanical hyperalgesia was observed in both fatigue and control groups after intramuscular injection of pH 4.0, but only the fatigue group after injection of pH 5. Neither the fatigue nor the control group developed hyperalgesia in response to intramuscular injection of pH 6 or pH 7.2. In conclusion, fatigue modified the susceptibility of mice to acid injection of pH 5.0 to result in mechanical hyperalgesia after 2 injections of pH 5.0. The fatigue task did not produce measurable changes in the muscle tissue suggesting a central mechanism mediating the enhancement of hyperalgesia.Perspective-These data therefore show that muscle fatigue can enhance the likelihood that one develops pain to a mild insult. Clinically, this could relate to the development of pain from such conditions as repetitive strain injury, and may relate to the interrelationship between chronic pain and fatigue. KeywordsFatigue; exercise; acid; protons; low-pH saline Pain arising from musculoskeletal disorders is a major clinical problem globally, 58 and fibromyalgia affects 2% of population in the United States. 57 As high as 76% of people with chronic widespread musculoskeletal pain conditions, such as fibromyalgia and arthritis, also report fatigue. 26 Conversely, as high as 94% of people with chronic fatigue syndrome report musculoskeletal pain and approximately half of the population has chronic widespread musculoskeletal pain. 56,60 Pain is increased during and after exercise in people with fibromyalgia and chronic fatigue syndrome. 20,48,54,55 Similarly, muscle fatigue is increased in people with chronic fatigue syndrome. 3,10,23 To assess mechanisms of chronic widespread pain, we developed an animal model that mimics the clinical symptoms. Two injections of acidic saline (pH 4.0), 5 days apart, into 1 muscle results in bilateral long-lasting hyperalgesia of the paw, 41 muscle,59 and the viscera28 without muscle tissue damage.41 The intramuscular pH decreases to a p...

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“…Thus understanding the molecular foundation for neuropathic pain is essential to facilitate the development of novel therapeutics. In PNS injury, TNF-α plays a central role, orchestrating many of the events involved in Wallerian degeneration and sensitizing nociceptors (31)(32)(33). In fact, neuropathic pain states have been modeled by direct administration of TNF-α into uninjured sciatic nerves (34,35).…”

Section: Introductionmentioning

confidence: 99%

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

Gaultier

Arandjelovic

et al. 2008

J. Clin. Invest.

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Injury to the peripheral nervous system (PNS) initiates a response controlled by multiple extracellular mediators, many of which contribute to the development of neuropathic pain. Schwann cells in an injured nerve demonstrate increased expression of LDL receptor-related protein-1 (LRP1), an endocytic receptor for diverse ligands and a cell survival factor. Here we report that a fragment of LRP1, in which a soluble or shed form of LRP1 with an intact α-chain (sLRP-α), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-α into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-α and IL-1β locally. sLRP-α also inhibited CCI-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultures of Schwann cells, astrocytes, and microglia, sLRP-α inhibited TNF-α-induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-α did not involve TNF-α binding, but rather glial cell preconditioning, so that the subsequent response to TNF-α was inhibited. Our results show that sLRP-α is biologically active and may attenuate neuropathic pain. In the PNS, the function of LRP1 may reflect the integrated activities of the membrane-anchored and shed forms of LRP1.

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Tumour necrosis factor-α induces ectopic activity in nociceptive primary afferent fibres

Cited by 477 publications

References 29 publications

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

Muscle Fatigue Increases the Probability of Developing Hyperalgesia in Mice

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

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