Abstract
BackgroundAlthough substance P (SP) is an important primary afferent modulator in nociceptive processes, it is unclear whether SP regulates its own release from primary sensory neurons.ResultsUsing a highly sensitive radioimmunoassay for SP, we have demonstrated that the activation of neurokinin-1 receptor by SP or GR73632 (a potent neurokinin-1 receptor agonist) triggered an increase of SP release from cultured adult rat dorsal root ganglion (DRG) neurons depending on the dose and exposure time within 60 min, and thereafter, the SP release level gradually decreased over 360 min. Accompanying the SP release, a significant reduction in the percentage of neurons expressing neurokinin-1 receptor on their membranes during exposure to SP (200 pg/dish) occurred time dependently (56 ± 5% and 32 ± 2% at 180 and 360 min, respectively). The GR73632-evoked (10 nM, 60 min) SP release was attenuated by several inhibitors for mitogen-activated protein kinase kinase, p38 mitogen-activated protein (MAP) kinase and cyclooxygenase-2 (COX-2), protein kinase C (PKC), respectively. In contrast, a c-Jun NH2-terminal kinase inhibitor increased the GR73632-evoked SP release.ConclusionThese results indicate that the neurokinin-1 receptor activation by its agonists regulates the SP release process involving the activation of MAP kinases, PKCs and COX-2 from cultured DRG neurons.
Highlights
Substance P (SP) is an important primary afferent modulator in nociceptive processes, it is unclear whether substance P (SP) regulates its own release from primary sensory neurons
The release of SP induced by itself from cultured rat dorsal root ganglion (DRG) neurons To investigate whether SP induces its own release from cultured DRG neurons, we examined the effects of SP on the release of SP in a dose- and time-dependent manner
The increase in the SP release evoked by itself was partially significantly attenuated by 1 μM CP-96,345 [19] and by 100 nM GR94800 [20], not by 1 μM SB222200 [20] as shown in Fig. 1C, whereas these antagonists did not have any effect when used alone (Data not Substance P release control substance P (200 pg/dish) substance P for 1 h
Summary
Substance P (SP) is an important primary afferent modulator in nociceptive processes, it is unclear whether SP regulates its own release from primary sensory neurons. SP has been shown to induce the activation of ERK1/2 and p38 mitogen-activated protein (MAP) kinases, nuclear factorkappa B and protein kinase C (PKC), and thereafter to increase the production of prostaglandin E2 and the expression of COX-2 [13,14,15] Both anatomical and functional evidence have suggested that neurokinin-1 receptors may function as auto-receptors in DRG neurons [16,17]. The objective of the present study is designed to demonstrate whether the release of SP may be stimulated by itself through the activation of its receptors and the involvement of some important intracellular effectors (such as MAP kinase, PLC and PKC, COX and PKA) from cultured DRG neurons
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