Elsevier

Neuroscience

Volume 81, Issue 1, 26 August 1997, Pages 255-262
Neuroscience

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

https://doi.org/10.1016/S0306-4522(97)00147-4Get rights and content

Abstract

Tumour necrosis factor-α, a pro-inflammatory cytokine, is expressed endoneurially following a variety of local and systemic pathophysiological insults which give rise to pain. We administered tumour necrosis factor-α to pentobarbital-anaesthetized rats, either topically along a restricted portion of the sciatic nerve or injected subcutaneously within the distribution of the sural nerve. Single nociceptive primary afferent fibres were assessed for ectopic discharge and receptor sensitization. Low concentrations (0.001–0.01 ng/ml) of tumour necrosis factor-α applied along the nerve elicited a dose-dependent, rapid onset (1–3 min) increase in discharge; higher concentrations led to reduced firing rates. C-fibres developed higher mean firing frequencies than Aδ-fibres. Bursting frequency in both fibre types reached several (>6) Hz. No change in mechanical threshold was observed. Intradermal injection (50 pg in 50 μl) led to ectopic discharge and a decrease in mechanical threshold; these effects developed at different rates, suggesting multiple actions of the cytokine.

Our data suggest that acute application of tumour necrosis factor-α to the axon can lead to aberrant electrophysiologic activity independent of peripheral receptor involvement. This low level of ectopic firing of nociceptive axons may produce wind-up in dorsal horn neurons or may, by itself, be interpreted as pain.

Section snippets

Subjects

Adult, male Sprague–Dawley (Harlan Sprague–Dawley, Indianapolis, IN) rats weighing 300–400 g were used in experimental procedures approved by the Animal Care and Use Committee of the University of California, San Diego. Sequential administration of ascending doses of TNF to the same fibre was employed in order to minimize animal use. Animals were housed two per cage with water and food pellets available ad libitum.

Surgical preparation

Rats were anaesthetized initially with 60 mg/kg i.p. of sodium pentobarbital. A

Paradigm I

Recordings were obtained from 19 primary afferent fibres with cutaneous mechanical receptive fields on the foot and toes. All fibres were initially silent; however, following removal of the saline and addition of 0.1% BSA in saline to the chamber, ongoing activity of up to 0.1 Hz was recorded (mean 0.04±0.01 Hz for Aδ-fibres, n=10; 0.03±0.01 Hz for C-fibres, n=9). Mean mechanical threshold of Aδ-fibres was 10.1±2.0 g (range 4–15). Aδ-fibres with hair input were not studied. Mean mechanical

Discussion

TNF at concentrations between 0.001 and 0.01 ng/ml applied to a 4 mm length of the rat sciatic nerve trunk elicited dose-dependent firing in individual sensory afferent fibres. The TNF-mediated increase in electrophysiological activity was more pronounced in C- than in Aδ-fibres and occurred in the absence of changes in peripheral receptive field mechanical threshold, indicating that systemic absorption and resultant changes in receptor transduction were not a factor in the TNF-evoked firing of

Conclusions

Our data suggest that TNF release in the vicinity of the axon, independent of involvement of its peripheral receptors, can lead to aberrant electrophysiological activity. In contrast, following exposure of the axon and nerve terminal to TNF both development of ongoing activity and receptor sensitization occur. These effects are independent of one another and appear to develop at different rates, suggesting multiple actions of the cytokine. Receptor sensitization has been postulated to be

Acknowledgements

The authors are grateful for discussion with Dr J. G. Cannon. This work was supported by NIH AR 42235 (LSS), NIH NS 18715 (RRM), F 32 NS10071 (RW) and the Department of Veterans Affairs (RRM).

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