Spontaneous Pain, Both Neuropathic and Inflammatory, Is Related to Frequency of Spontaneous Firing in Intact C-Fiber Nociceptors

Djouhri, Laiche; Koutsikou, Stella; Fang, Xin; McMullan, Simon; Lawson, Sally N.

doi:10.1523/jneurosci.3388-05.2006

Cited by 382 publications

(457 citation statements)

References 43 publications

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“…For our first model, we used intraplantar injection of CFA, which consists of a mixture of paraffin oil (85% vol/vol), mannide monooleate (15% vol/vol), and heatkilled Mycobacteria tuberculosis (1 mg/mL), and is an immunological adjuvant (13)(14)(15). Second, we chose a modified plantar incision (injury to the skin and underlying muscle) to model sterile tissue injury-based inflammation (16)(17)(18).…”

Section: Resultsmentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

152

135

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Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund's adjuvant (CFA) as a model of adjuvant-and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G + CD11b + neutrophils and T-cell receptor (TCR) β + T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b + Ly6G − myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2 + Ly6C hi ) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b + Ly6G − myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation.pain | inflammation | cytokines | monocytes | macrophages

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Section: Resultsmentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

152

135

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“…Following the CFA injection, thermal hyperalgesia and mechanical allodynia were analyzed with Hargreaves and von Frey tests, respectively, at days 1, 2, 3, 4, and 10. The spontaneous pain assessment was performed in a modified version (Djouhri et al, 2006). Briefly, 20 l of CFA was injected into the side of the right knee and the plantar surface of the right paw.…”

Section: Methodsmentioning

confidence: 99%

Small RNAs Control Sodium Channel Expression, Nociceptor Excitability, and Pain Thresholds

Zhao¹,

Lee²,

Momin³

et al. 2010

J. Neurosci.

157

129

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To examine the role of small RNAs in peripheral pain pathways, we deleted the enzyme Dicer in mouse postmitotic damage-sensing neurons. We used a Nav1.8-Cre mouse to target those nociceptors important for inflammatory pain. The conditional null mice were healthy with a normal number of sensory neurons and normal acute pain thresholds. Behavioral studies showed that inflammatory pain was attenuated or abolished. Inflammatory mediators failed to enhance excitability of Nav1.8 ϩ sensory neurons from null mutant mice. Acute noxious input into the dorsal horn of the spinal cord was apparently normal, but the increased input associated with inflammatory pain measured using c-Fos staining was diminished. Microarray and quantitative real-time reverse-transcription PCR (qRT-PCR) analysis showed that Dicer deletion lead to the upregulation of many broadly expressed mRNA transcripts in dorsal root ganglia. By contrast, nociceptor-associated mRNA transcripts (e.g., Nav1.8, P2xr3, and Runx-1) were downregulated, resulting in lower levels of protein and functional expression. qRT-PCR analysis also showed lowered levels of expression of nociceptor-specific pre-mRNA transcripts. MicroRNA microarray and deep sequencing identified known and novel nociceptor microRNAs in mouse Nav1.8 ϩ sensory neurons that may regulate nociceptor gene expression.

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“…Ectopic discharge in sensory fibers in models of peripheral neuropathy has been proposed in a number of models (Djouhri et al, 2006;Han et al, 2000;Liu et al, 2000c). Several studies have reported that systemic administration of lidocaine decreases ectopic activity recorded from injured peripheral sensory fibers (Chabal et al, 1989;Devor et al,1992;Omana-Zapata et al,1997a;Sotgiu et al, 1992) and reduces neuropathic pain (Brochu et al, 2006;Erichsen et al, 2003;Sinnott et al, 1999;Smith et al, 2002).…”

Section: Contribution Of Peripheral Drive To Spontaneous Activity Of mentioning

confidence: 99%

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

Pitcher

Henry

2008

Experimental Neurology

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Previously we reported that the cuff model of peripheral neuropathy, in which a 2 mm polyethylene tube is implanted around the sciatic nerve, exhibits aspects of neuropathic pain behavior in rats similar to those in humans and causes robust hyperexcitation of spinal nociceptive dorsal horn neurons. The mechanisms mediating this increased excitation are not known and remain a key unresolved question in models of peripheral neuropathy. In anesthetized adult male Sprague-Dawley rats 2-6 weeks after cuff implantation we found that elevated discharge rate of single lumbar (L 3-4 ) wide dynamic range (WDR) neurons persists despite acute spinal transection (T9) but is reversed by local conduction block of the cuff-implanted sciatic nerve; lidocaine applied distal to the cuff (i.e. between the cuff and the cutaneous receptive field) decreased spontaneous baseline discharge of WDR dorsal horn neurons ~40% (n=18) and when applied subsequently proximal to the cuff, i.e. between the cuff and the spinal cord, it further reduced spontaneous discharge by ~60% (n=19; P<0.05 proximal vs. distal) to a level that was not significantly different from that of naive rats. Furthermore, in cuff-implanted rats WDR neurons (n=5) responded to mechanical cutaneous stimulation with an exaggerated afterdischarge which was reversed entirely by proximal nerve conduction block. These results demonstrate that the hyperexcited state of spinal dorsal horn neurons observed in this model of peripheral neuropathy is not maintained by tonic descending facilitatory mechanisms. Rather, on-going afferent discharges originating from the sciatic nerve distal to, at, and proximal to the cuff maintain the synapticallymediated gain in discharge of spinal dorsal horn WDR neurons and hyperresponsiveness of these neurons to cutaneous stimulation. Our findings reveal that ectopic afferent activity from multiple regions along peripheral nerves may drive CNS changes and the symptoms of pain associated with peripheral neuropathy.

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Spontaneous Pain, Both Neuropathic and Inflammatory, Is Related to Frequency of Spontaneous Firing in Intact C-Fiber Nociceptors

Abstract: Spontaneous pain, a poorly understood aspect of human neuropathic pain, is indicated in animals by spontaneous foot lifting (SFL).

Cited by 382 publications

References 43 publications

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Small RNAs Control Sodium Channel Expression, Nociceptor Excitability, and Pain Thresholds

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

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Spontaneous Pain, Both Neuropathic and Inflammatory, Is Related to Frequency of Spontaneous Firing in Intact C-Fiber Nociceptors

Abstract: Spontaneous pain, a poorly understood aspect of human neuropathic pain, is indicated in animals by spontaneous foot lifting (SFL).

Cited by 382 publications

References 43 publications

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

Small RNAs Control Sodium Channel Expression, Nociceptor Excitability, and Pain Thresholds

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

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CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity