The Effect of Nimodipine on Calcium Homeostasis and Pain Sensitivity in Diabetic Rats
- 143 Downloads
1. The pathogenesis of diabetic neuropathy is a complex phenomenon, the mechanisms of which are not fully understood. Our previous studies have shown that the intracellular calcium signaling is impaired in primary and secondary nociceptive neurons in rats with streptozotocin (STZ)-induced diabetes. Here, we investigated the effect of prolonged treatment with the L-type calcium channel blocker nimodipine on diabetes-induced changes in neuronal calcium signaling and pain sensitivity.
2. Diabetes was induced in young rats (21 p.d.) by a streptozotocin injection. After 3 weeks of diabetes development, the rats were treated with nimodipine for another 3 weeks. The effect of nimodipine treatment on calcium homeostasis in nociceptive dorsal root ganglion neurons (DRG) and substantia gelatinosa (SG) neurons of the spinal cord slices was examined with fluorescent imaging technique.
3. Nimodipine treatment was not able to normalize elevated resting intracellular calcium ([Ca2+] i ) levels in small DRG neurons. However, it was able to restore impaired Ca2+ release from the ER, induced by either activation of ryanodine receptors or by receptor-independent mechanism in both DRG and SG neurons.
4. The beneficiary effects of nimodipine treatment on [Ca2+] i signaling were paralleled with the reversal of diabetes-induced thermal hypoalgesia and normalization of the acute phase of the response to formalin injection. Nimodipine treatment was also able to shorten the duration of the tonic phase of formalin response to the control values.
5. To separate vasodilating effect of nimodipine Biessels et al., (Brain Res. 1035:86–93) from its effect on neuronal Ca2+ channels, a group of STZ-diabetic rats was treated with vasodilator – enalapril. Enalapril treatment also have some beneficial effect on normalizing Ca2+ release from the ER, however, it was far less explicit than the normalizing effect of nimodipine. Effect of enalapril treatment on nociceptive behavioral responses was also much less pronounced. It partially reversed diabetes-induced thermal hypoalgesia, but did not change the characteristics of the response to formalin injection.
6. The results of this study suggest that chronic nimodipine treatment may be effective in restoring diabetes-impaired neuronal calcium homeostasis as well as reduction of diabetes-induced thermal hypoalgesia and noxious stimuli responses. The nimodipine effect is mediated through a direct neuronal action combined with some vascular mechanism.
KEY WORDS:nimodipine enalapril calcium dorsal horn neurons dorsal root ganglion endoplasmic reticulum
This work was supported by Juvenile Diabetes Research Foundation grant #1-2004-30 to NV.
- Bowersox, S. S., Gadbois, T., Singh, T., Pettus, M., Wang, Y. X., and Luther, R. R. (1996). Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain. J. Pharmacol. Exp. Ther. 279:1243–1249.PubMedGoogle Scholar
- Brewster, W. J., Fernyhough, P., Diemel, L. T., Mohiuddin, L., and Tomlinson, D. R. (1995). Changes in nerve growth factor and preprotachykinin messenger RNA levels in the iris and trigeminal ganglion in diabetic rats: Effects of treatment with insulin or nerve growth factor. Mol. Brain Res. 29:131–139.CrossRefPubMedGoogle Scholar
- Greene, D. A., Chakrabarti, S., Lattimer, S. A., and Sima, A. A. (1987). Role of sorbitol accumulation and myo-inositol depletion in paranodal swelling of large myelinated nerve fibers in the insulin-deficient spontaneously diabetic bio-breeding rat. Reversal by insulin replacement, an aldose reductase inhibitor, and myo-inositol. J. Clin. Invest. 79:1479–1485.PubMedCrossRefGoogle Scholar
- Hall, K. E., Liu, J., Sima, A. A., and Wiley, J. W. (2001). Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathy. J. Europhysiol. 86:760–770.Google Scholar
- Mancia, G., Omboni, S., Agabiti-Rosei, E., Casati, R., Fogari, R., Leonetti, G., Montemurro, G., Nami, R., Pessina, A. C., Pirrelli, A., and Zanchetti, A. (2000). Antihypertensive efficacy of manidipine and enalapril in hypertensive diabetic patients. J. Cardiovasc. Pharmacol. 35:926–931.CrossRefPubMedGoogle Scholar
- Manschot, S. M., Biessels, G. J., Cameron, N. E., Cotter, M. A., Kamal, A., Kappelle, L. J., and Gispen, W. H. (2003a). Angiotensin converting enzyme inhibition partially prevents deficits in water maze performance, hippocampal synaptic plasticity and cerebral blood flow in streptozotocin-diabetic rats. Brain Res. 966:274–282.CrossRefPubMedGoogle Scholar
- Manschot, S. M., Gispen, W. H., Kappelle, L. J., and Biessels, G. J. (2003b). Nerve conduction velocity and evoked potential latencies in streptozotocin-diabetic rats: Effects of treatment with an angiotensin converting enzyme inhibitor. Diabetes Metab. Res. Rev. 19:469–477.CrossRefPubMedGoogle Scholar
- Neugebauer, V., Vanegas, H., Nebe, J., Rumenapp, P., and Schaible, H. G. (1996). Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint. J. Neurophysiol. 76:3740–3749.PubMedGoogle Scholar
- Ouardouz, M., Nikolaeva, M. A., Coderre, E., Zamponi, G. W., McRory, J. E., Trapp, B. D., Yin, X., Wang, W., Woulfe, J., and Stys, P. K. (2003). Depolarization-induced Ca2+ release in ischemic spinal cord white matter involves L-type Ca2+ channel activation of ryanodine receptors. Neuron 40:53–63.CrossRefPubMedGoogle Scholar
- Tuomilehto, J., Rastenyte, D., Birkenhдger, W. H., Thijs, L., Antikainen, R., Bulpitt, C. J., Fletcher, A. E., Forette, F., Goldhaber, A., Palatini, P., Sarti, C., and Fagard, R. (1999). Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N. Engl. J. Med. 340:677–684.CrossRefPubMedGoogle Scholar