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Contribution of interleukin‐1β to the inflammation‐induced increase in nerve growth factor levels and inflammatory hyperalgesia
Author(s) -
SafiehGarabedian Bared,
Poole Stephen,
Allchorne Andrew,
Winter Janet,
Woolf Clifford J.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15035.x
Subject(s) - hyperalgesia , dexamethasone , inflammation , nerve growth factor , endocrinology , medicine , calcitonin gene related peptide , dorsal root ganglion , freund's adjuvant , substance p , calcitonin , pharmacology , cytokine , nociception , neuropeptide , spinal cord , receptor , psychiatry
1 Peripheral inflammation is associated with the local production of neuroactive inflammatory cytokines and growth factors. These may contribute to inflammatory pain and hyperalgesia by directly or indirectly altering the function or chemical phenotype of responsive primary sensory neurones. 2 To investigate this, inflammation was produced by the intraplantar injection of complete Freund's adjuvant (CFA) in adult rats. This resulted in a significant elevation in interleukin‐ip (IL‐1β) and nerve growth factor (NGF) levels in the inflamed tissue and of the peptides, substance P and calcitonin gene‐related peptide (CGRP) in the L4 dorsal root ganglion 48 h post CFA injection. 3 The effects of a steroidal (dexamethasone) and a non‐steroidal (indomethacin) anti‐inflammatory drug on the levels of NGF and IL‐1β in inflamed tissue were investigated and compared with alterations in behavioural hyperalgesia and neuropeptide expression in sensory neurones. 4 Systemic dexamethasone (120 μg kg −1 per day starting the day before the CFA injection) had no effect on the inflammatory hyperalgesia. When the dose was administered 3 times daily, a reduction in mechanical and to a lesser extent thermal sensitivity occurred. Indomethacin at 2 mg kg −1 daily (i.p.) had no effect on the hyperalgesia and a dose of 4 mg kg −1 daily was required to reduce significantly mechanical and thermal hypersensitivity. 5 The increase in NGF produced by the CFA inflammation was prevented by both dexamethasone and indomethacin, but only at the higher dose levels. Dexamethasone at the lower and higher dose regimes diminished the upregulation of IL‐1β whereas indomethacin had an effect only at the higher dose. 6 The increase in SP and CGRP levels produced by the CFA inflammation was prevented by dexamethasone and indomethacin at the lower and higher dose regimes. 7 Intraplantar injections of IL‐1β (0.01, 0.1 and 1 ng) produced a brief (6 h) thermal hyperalgesia and an elevation in cutaneous NGF levels which was prevented by pretreatment with human recombinant IL‐1 receptor antagonist (IL‐1 ra) (0.625 μg, i.v.). The thermal hyperalgesia but not the NGF elevation produced by intraplantar IL‐1β (1 ng) was prevented by administration of a polyclonal neutralizing anti‐NGF serum. 8 IL‐1 ra significantly reduced the mechanical hyperalgesia produced by CFA for 6 h after administration as well as the CFA‐induced elevation in NGF levels. Anti‐NGF pretreatment substantially reduced CFA‐induced mechanical and thermal hyperalgesia without reducing the elevation in IL‐1β. 9 Intraplantar NGF (0.O 2 , 0.2 and 2 μg) injections produced a short lasting thermal and mechanical hyperalgesia but did not change IL‐1β levels in the hindpaw skin. 10 Our results demonstrate that IL‐1β contributes to the upregulation of NGF during inflammation and that NGF has a major role in the production of inflammatory pain hypersensitivity.