Intrathecal substance P-induced thermal hyperalgesia and spinal release of prostaglandin E 2 and amino acids

Abstract

Substance P is an important neuromediator in spinal synaptic transmission, particularly in processing nociceptive afferent information. The effects of substance P are mediated by activation of the neurokinin I receptor. Evidence has suggested that excitatory amino acids such as glutamate, and prostaglandins including prostaglandin E 2 are involved in the enhanced spinal excitability and hyper-algesia produced by spinal substance P. In the present study, we have demonstrated that intrathecal injection of substance P (20 nmol) in rats chronically implanted with intrathecal dialysis catheters induced a decrease in thermal paw withdrawal latency (before: 10.4 ± 0.3 s; after 7.6 ± 0.6 s), which was accompanied by an increase in prostaglandin E 2 (362 ± 37% of baseline), glutamate (267 ± 84%) and taurine (279 ± 57%), but not glycine, glutamine, serine or asparagine. Intrathecal injection of artificial cerebrospinal fluid had no effect upon the behavior or release. Substance P-induced thermal hyperalgesia and prostaglandin E 2 release were significantly attenuated by a selective neurokinin 1 receptor antagonist RP67580, but not by an enantiomer RP68651. However, substance P-induced release of glutamate and taurine was not reduced by treatment with RP67580. SR140333, another neurokinin 1 receptor antagonist, displayed the same effects as RP67580 (i.e. block of thermal hyperalgesia and prostaglandin E 2 release, but not release of amino acids). These results provide direct evidence suggesting that the spinal substance P-induced thermal hyper-algesia is mediated by an increase in spinal prostaglandin E 2 via activation of the neurokinin 1 receptor. These findings define an important linkage between small afferents, sensory neurotransmitter release and spinal prostanoids in the cascade of spinally-mediated hyperalgesia. The evoked release of glutamate is apparently not a result of activation of neurokinin 1 receptors. Accordingly, consistent with other pharmacological data, acute spinal glutamate release does not contribute to the hyperalgesia induced by activation of spinal neurokinin 1 receptors.