Adjuvant-induced joint inflammation causes very rapid transcription of beta-preprotachykinin and alpha-CGRP genes in innervating sensory ganglia.
Neuropeptides synthesized in dorsal root ganglia (DRG) have been implicated in neurogenic inflammation and nociception in experimental and clinical inflammatory arthritis. We examined the very early changes in response to adjuvant injection in a rat model of unilateral tibio-tarsal joint inflammation and subsequent monoarthritis. Within 30 min of adjuvant injection ipsilateral swelling and hyperalgesia were apparent, and marked increases in beta-preprotachykinin-A (beta-PPT-A) and alpha-calcitonin gene-related peptide (CGRP)-encoding mRNAs were observed in small-diameter L5 DRG neurones innervating the affected joint. This response was augmented by recruitment of additional small-diameter DRG neurones expressing beta-PPT-A and CGRP transcripts. The increased mRNA was paralleled by initial increases in L5 DRG content of the protein products, substance P and calcitonin gene-related peptide. Within 15 min of adjuvant injection there were increases in electrical activity in sensory nerves innervating a joint. Blockade of this activity prevented the rapid induction in beta-PPT-A and CGRP mRNA expression in DRG neurones. Increased expression of heteronuclear (intron E) beta-PPT-A RNA suggests that increases in beta-PPT-A mRNA levels were, at least in part, due to transcription. Pre-treatment with the protein synthesis inhibitor cycloheximide had no effect upon the early rise in neuropeptide mRNAS: This and the rapid time course of these changes suggest that increased sensory neural discharge and activation of a latent modulator of transcription are involved.
Bulling
D G
DG
Molecular Endocrinology, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK.
Kelly
D
D
Bond
S
S
McQueen
D S
DS
Seckl
J R
JR
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D048429:Cell Size; D003513:Cycloheximide / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017403:In Situ Hybridization; D007267:Injections; D008297:Male; D009475:Neurons, Afferent / Q000378:metabolism; D011312:Pressure / Q000009:adverse effects; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D013373:Substance P / Q000032:analysis; D009435:Synaptic Transmission / Q000187:drug effects; D015320:Tachykinins / Q000096:biosynthesis* / Q000235:genetics; D013643:Tarsus, Animal / Q000294:innervation; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
D011498:Protein Precursors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; D005620:Freund's Adjuvant; D003513:Cycloheximide; D015740:Calcitonin Gene-Related Peptide