ABSTRACT
Sensory neurons in the dorsal root ganglion express two kinds of tetrodotoxin resistant (TTX-R) isoforms of voltage-gated sodium channels, Na(V)1.8 and Na(V)1.9. These isoforms play key roles in the pathophysiology of chronic pain. Of special interest is Na(V)1.9: our previous studies revealed a unique property of the Na(V)1.9 current, i.e., the Na(V)1.9 current shows a gradual and notable up-regulation of the peak amplitude during recording ("spontaneous augmentation of Na(V)1.9"). However, the mechanism underlying the spontaneous augmentation of Na(V)1.9 is still unclear. In this study, we examined the effects of protein kinases A and C (PKA and PKC), on the spontaneous augmentation of Na(V)1.9. The spontaneous augmentation of the Na(V)1.9 current was significantly suppressed by activation of PKA, whereas activation of PKA did not affect the voltage dependence of inactivation for the Na(V)1.9 current. On the contrary, the finding that activation of PKC can affect the voltage dependence of inactivation for Na(V)1.9 in the perforated patch recordings, where the augmentation does not occur, suggests that the effects of PMA are independent of the augmentation process. These results indicate that the spontaneous augmentation of Na(V)1.9 was regulated directly by PKA, and indirectly by PKC.
Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Ganglia, Spinal/metabolism , Neurons, Afferent/enzymology , Protein Kinase C/metabolism , Sodium Channels/metabolism , Animals , Cells, Cultured , Enzyme Activators/pharmacology , Enzyme Inhibitors/pharmacology , Mice , Neurons, Afferent/drug effects , Sodium Channels/drug effectsABSTRACT
AIMS: The analgesic effects of moxibustion on an experimental model of osteoarthritis of the knee were investigated. METHODS: Male Wistar rats (n=36, 296-421 g) were used. Intra-articular injection of mono-iodoacetic acid (MIA) was performed to induce knee osteoarthritis. Indirect moxibustion was applied to the lateral aspect of the knee joint every other day for 28 days (14 treatments). Weight bearing of the hind legs was measured directly by the downward pressure applied to footplates, using an Incapacitance Tester. Morphine was injected for testing the validity of weight bearing as a pain measure, and naloxone was used to examine the participation of endogenous opioids in the mechanism of moxibustion analgesia. Data were analysed by calculating the area under the curve. RESULTS: Injection of MIA significantly reduced weight bearing. No analgesic effects of moxibustion were observed during the initial 7 days (unpaired t test, P=0.83). Continued moxibustion treatments increased weight bearing at the 14th day significantly, and this effect continued until the end of the experiment on the 28th day (P<0.05). A single moxibustion treatment had no immediate effect on weight bearing. The analgesia due to the cumulative effect of moxibustion was antagonised by naloxone injection. Morphine injection in control MIA injected rats increased weight bearing to the normal range, confirming the validity of the measurements. CONCLUSIONS: These results highlight the importance of repeated moxibustion treatments for pain relief in experimental knee osteoarthritis and suggest the existence of sustained inhibitory modulation by endogenous opioids in the moxibustion group.
