Clonidine reduces hypersensitivity and alters the balance of pro- and anti-inflammatory leukocytes after local injection at the site of inflammatory neuritis.
Perineural alpha2-adrenoceptor activation relieves hypersensitivity induced by peripheral nerve injury or sciatic inflammatory neuritis. This effect is associated with a reduction in pro-inflammatory cytokines, as well as a reduction in local leukocyte number and their capacity to produce pro-inflammatory cytokines. Curiously, clonidine's antinociceptive effect appears with a 2-3-day delay after injection. Previous observations have shown that alpha-adrenoceptor activation induces apoptosis in leukocytes, which would reduce leukocyte number. Additionally, macrophage scavenging of apoptotic cells results in a shift to an anti-inflammatory phenotype, with expression of transforming growth factor (TGF)-beta1. We therefore examined the effects of perineural clonidine 24 h and 3 days after its injection on apoptosis, TGF-beta1 expression and lymphocyte and macrophage phenotype in acute sciatic inflammatory neuritis. Perineural clonidine reduced ipsilateral neuritis-induced hypersensitivity in a delayed manner (3 days after treatment), along with a reduction at this time in lymphocyte number and an increase in caspase-3 and TGF-beta1 expressing cells and macrophages co-expressing TGF-beta1 in the sciatic nerve. One day after injection clonidine treatment was associated with a reduction in lymphocytes and pro-inflammatory Th-1 cells as well as increased numbers of caspase-3 and TGF-beta1 expressing cells and macrophages co-expressing TGF-beta1 in sciatic nerve. Clonidine's effects were prevented by co-administration of an alpha2-adrenoceptor antagonist. These data suggest that alpha2-adrenoceptor activation in sciatic inflammatory neuritis increases local apoptosis and anti-inflammatory products early after treatment. This early effect likely underlies the delayed anti-inflammatory and anti-hypersensitivity effects of perineural clonidine in this setting.
Romero-Sandoval
Alfonso
A
Department of Anesthesiology and Center for the Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009, USA.
Eisenach
James C
JC
D000316:Adrenergic alpha-Agonists / Q000276:immunology / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000704:Analysis of Variance; D000772:Anesthesia, Local; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D003000:Clonidine / Q000276:immunology / Q000494:pharmacology*; D004195:Disease Models, Animal; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D020426:Sciatic Neuropathy / Q000276:immunology* / Q000517:prevention & control; D018709:Statistics, Nonparametric; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000276:immunology
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D053773:Transforming Growth Factor beta1; D053148:Caspase 3; D003000:Clonidine