Pain modulatory actions of cytokines and prostaglandin E2 in the brain.
Proinflammatory cytokines such as IL-1, IL-6, and TNF alpha are known to enhance nociception at peripheral inflammatory tissues. These cytokines are also produced in the brain. We found that an intracerebroventricular injection of IL-1 beta only at nonpyrogenic doses in rats reduced the paw-withdrawal latency on a hot plate and enhanced the responses of the wide dynamic range neurons in the trigeminal nucleus caudalis to noxious stimuli. This hyperalgesia, as assessed by behavioral and neuronal responses, was blocked by pretreatment with IL-1 receptor antagonist (IL-1Ra), Na salicylate, or alpha melanocyte-stimulating hormone, indicating the involvement of IL-1 receptors and the synthesis of prostanoids. IL-6 and TNF alpha at nonpyrogenic doses also induced hyperalgesia in a prostanoid-dependent way. Furthermore, the preoptic area (POA) was most sensitive to IL-1 beta (5-50 pg/kg) in the induction of behavioral hyperalgesia. The maximal response was obtained 30 min after injection of IL-1 beta at 20 pg/kg. On the other hand, an injection of IL-1 beta (20-50 pg/kg) into the ventromedial hypothalamus (VMH) prolonged the paw-withdrawal latency maximally 10 min after injection. This analgesia, as well as the intraPOA IL-1 beta-induced hyperalgesia, was completely blocked by IL-1Ra or Na salicylate. Our previous study has revealed that i.c.v. injection of PGE2 induces hyperalgesia through EP3 receptors and analgesia through EP1 receptors by its central action. The results, taken together, suggest (1) that IL-1 beta at lower doses in the brain induces hyperalgesia through EP3 receptors in the POA and (2) that the higher doses of brain IL-1 beta produces analgesia through EP1 receptors, probably, in the VMH.
Hori
T
T
Department of Physiology, Kyushu University Faculty of Medicine, Fukuoka, Japan.
Oka
T
T
Hosoi
M
M
Aou
S
S
D000818:Animals; D001921:Brain / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced; D007276:Injections, Intraventricular; D009619:Nociceptors / Q000187:drug effects; D010146:Pain / Q000503:physiopathology*
D016207:Cytokines; D015232:Dinoprostone