Inflammation Induces Ectopic Mechanical Sensitivity in Axons of Nociceptors Innervating Deep Tissues

Viktig studie som nevner hvordan betennelser i nervene gir lavere terskel for nociceptiv avfyring, altså smerte selv ved lette trykk, og kan gi spontane avfyringer, altså smerte uten noen fysiologisk årsak.

«Here we show that inflammation led to mechanical sensitivity of the axons of a subset of mechanically sensitive primary sensory neurons. Dorsal root recordings were made from 194 mechanically sensitive neurons that innervated deep and cutaneous structures and had C, Aδ, and Aαβ conduction velocities. »

«However, the axons of neurons innervating deep structures and having C- or Aδ-conduction velocities became mechanically sensitive during the neuritis, and also exhibited an increased incidence of spontaneous discharge. »

«However, the axons of neurons innervating deep structures and having C- or Aδ-conduction velocities became mechanically sensitive during the neuritis, and also exhibited an increased incidence of spontaneous discharge. »

«Primary sensory neurons are considered to “sense” only at their endings, within the structure they innervate. Sensory quality and localization are normally initiated by the activation of modality-specific sensory transducers in the tissue being stimulated, resulting in action potentials that are carried by axons, bundled in nerves, to the CNS. However, in many human patients, movements of intact, apparently uninjured nerves far from the innervated tissue can elicit radiating pain (e.g., “sciatica”). Such movement-induced radiating pain could be explained by the induction of ectopic sensory function along the axon.»

Svært viktig sitat som nevner at dette ikke gjelder i huden, men i dypere nivåer av kroppen.
«Using extracellular recording techniques in a model of neuritis, we now report that inflammation of intact axons leads to axonal mechanical sensitivity. We found that this phenomenon was limited to slowly conducting axons innervating noncutaneous structures.»
«Deep RFs were identified through the skin and proved by moving the overlying skin and repeating the effective stimulus to the same underlying spot, through a different portion of skin. »

«Action potentials in the absence of evident or applied stimuli are termed ongoing activity(OA). Ongoing activity was recorded for 2 min after the RF was located, and after mechanical stimulation of the nerve. During CFA neuritis, more deep neurons with C- and Aδ-axons had OA (19/111) than did cutaneous neurons with C- and Aδ-axons recorded during the same experiments [2/43; P < 0.05 (chi-square)], or than did deep neurons with C- and Aδ-axons recorded during the control experiment [1/27; P = 0.05 (Fisher’s exact)]. »

Betennelser i nervene gir hypeaemi, økt blodgjennomgstrømning. Dette er nok bare i akuttfasen.
«At 7 days postoperatively, the affected section of the nerve was characterized by encasement with granulation tissue and hyperemia of the intrinsic vasculature. Histology of the lesion demonstrated epineurial edema, increased lymphocytes, and a massive infiltration of macrophages within the epineurium and the granuloma (Fig. 4, B, D, and F). »

«These data demonstrate that neurons innervating deep structures and having properties of nociceptors (i.e., slow conduction velocities and high mechanical activation thresholds) developed axonal mechanical sensitivity during neuritis. »

«We employed noxious stimuli in the search for receptive fields, and thus especially for deep neurons, the tissues containing the terminals were often swollen, and therefore inflamed, before identification. Such inflammation is likely to reveal the latent receptive fields of otherwise silent nociceptors (Kress et al. 1992), making specific identification of such neurons improbable. Inflammation is also known to induce ongoing activity. Although we observed a statistically significant, increased incidence of ongoing activity in deep neurons during neuritis, these data must also be considered carefully because of the methodology used to identify the receptive fields. With these data, we cannot rule out that the axons of silent nociceptors from either deep or cutaneous tissues become mechanically sensitive during neuritis.»

«The development of axonal mechanical sensitivity was induced by local inflammation, which was characterized by the recruitment of epineurial macrophages and lymphocytes. This cellular infiltrate may play a key role in the axonal mechanical sensitivity. These cells lead to increased levels of tumor necrosis factor alpha, which increases sodium conductance in mammalian cell membranes (Hribar et al. 1999) and induces spontaneous activity in nociceptors when applied to axons (Leem and Bove 2002; Sorkin et al. 1997). »

«Second, the membrane potential in sensory neurons oscillates, dependent on Na+ channels, and normally approaches but does not reach the triggering threshold of the neuron (Amir et al. 1999). These oscillations become greater as the membrane is depolarized (Amir et al. 1999). Such oscillations would be potentiated by increased sodium conductance or sodium current, and could lead to spontaneous activity. Importantly, these oscillations are more pronounced in neurons innervating noncutaneous structures (Liu et al. 2002), which may be the basis for our observations that only the axons of noncutaneous neurons became mechanically sensitive.»

«Moreover, cutaneous allodynia seems dependent on at least transient activation of slowly conducting axons (Vatine et al. 1998). These findings, and ours, suggest that the observed sensitivity change was related to changes in the sensitivity of higher-order neurons that receive convergent information from the noncutaneous peripheral neurons that were sensitized by the neuritis. Alternatively, the cutaneous sensitivity may have been secondary to changes in ongoing activity of silent nociceptors (not specifically recorded from, as discussed above), or transient changes in neurons with faster conducting axons, which were not tested before or at the peak of heightened cutaneous sensitivity.»

«The appearance of axonal mechanical sensitivity during neuritis is consistent with reports of typically deep pain radiation provoked by mechanical stimulation of inflamed human dorsal roots (Kuslich et al. 1991; Smyth and Wright 1958; G. M. Bove and Z. H. Bajwa, unpublished observations), and radiating deep pain in the apparent absence of nerve injury (Verdugo and Ochoa 1993). »

Nevner at betente nerver er viktig forståelse for å forklare symptomene som kommer med sykdommer som har betennelser som utgangspunkt.
«Neuritis has long been recognized as a common malady of the peripheral nervous system (Gowers 1886), and can occur as a result of direct nerve injury or by extension from other diseases with inflammatory components, such as diabetes and endometriosis (Dyck et al. 2000; Zager et al. 1998). »

«Neuritis may be a common denominator in these otherwise seemingly unrelated disorders. The development of axonal mechanical sensitivity seems necessary to explain some clinical features of patients with radiating pain worsened by movements (e.g., “sciatica”), suffered by more than one-half of the population at some point in their lives (Frymoyer et al. 1983; Hult 1954).»

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