The Effect of Nimodipine on Calcium Homeostasis and Pain Sensitivity in Diabetic Rats

Abstract

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 ([Ca(2+)]( i )) levels in small DRG neurons. However, it was able to restore impaired Ca(2+) 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 [Ca(2+)]( 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 Ca(2+) channels, a group of STZ-diabetic rats was treated with vasodilator - enalapril. Enalapril treatment also have some beneficial effect on normalizing Ca(2+) 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.

Calcium Activity of Upper Thoracic Dorsal Root Ganglion Neurons in Zucker Diabetic Fatty Rats

“…This is in accordance with several other studies performed on DRG neurons from STZ-diabetic mice and rats, db/db diabetic mice and BB/W rats [18, 29–32], and on dorsal horn neurons from lumbar L 6 –L 7 spinal cord segments from STZ-diabetic rats [19, 33]. Shutov et al [34], however, have found an increased baseline [Ca 2+ ] i in L 4 –L 6 DRG neurons from STZ-induced diabetic rats at the same time as an unaltered baseline in DH neurons, suggesting a differential effect by diabetes on primary and secondary neurons [34]. The segmental location of the neurons investigated also appear to be affected differently by diabetes as neurons with longer axons are more susceptible to neuropathic changes than neurons with shorter axons [8].…”

Abnormal calcium homeostasis in peripheral neuropathies

“…Steady state cytoplasmic Ca 2+ levels are elevated in peripheral neurons of rodent models of diabetic neuropathy [41, 126, 127], most likely due to a impaired regulation of Ca 2+ homeostasis by pumps in the cell membrane, ER and mitochondria that are discussed above in the context of degenerative diabetic neuropathy. Systemic delivery of agents intended to restore neuronal Ca 2+ homeostasis have been reported to ameliorate indices of hyperalgesia in models of chemotherapeutic-induced neuropathy [128] and painful diabetic neuropathy [129–131], although the location and precise mechanisms of action remain to be determined.…”

Transmission of nociceptive signalling and mechanisms underlying its modulation

“…Thus, the role of Ltype calcium channels in small (nociceptive) DRG neurons is rather great. It should be mentioned that the effect was clearly pronounced in the case of rapid application of nimodipin, but when applications were slow, changes in Ca 2+ transients were smaller and demonstrated slow dynamics [4,10]. These findings allow one to hypothesize that agents belonging to the group of dihydropyridines may be effective in the case of pain syndromes accompanying diabetic neuropathy and that L-type calcium channels play a great role in the processes of transduction of nociceptive information.…”