Taurine replacement attenuates hyperalgesia and abnormal calcium signaling in sensory neurons of STZ-D rats

Abstract

The etiology of painful diabetic neuropathy is poorly understood, but may result from neuronal hyperexcitability secondary to alterations of Ca2+ signaling in sensory neurons. The naturally occurring amino acid taurine functions as an osmolyte, antioxidant, Ca2+ modulator, inhibitory neurotransmitter, and analgesic such that its depletion in diabetes may predispose one to neuronal hyperexcitability and pain. This study reports the effects of taurine replacement on hyperalgesia and sensory neuron Ca2+ homeostasis in streptozotocin-diabetic (STZ-D) rats. Nondiabetic and STZ-D rats were treated with a 2% taurine-supplemented diet for 6-12 wk. Thermal hyperalgesia and mechanical allodynia were determined by measuring hindpaw withdrawal latency to radiant heat and the withdrawal threshold to the von Frey anesthesiometer. Intracellular Ca2+ signaling was explored in neurons from L4-L6 dorsal root ganglia (DRG), using fura 2 fluorescence. Taurine replacement of diabetic rats attenuated deficits of nerve conduction and prevented reductions of mechanical and thermal withdrawal threshold and latency, respectively. In small DRG sensory neurons from diabetic rats, recovery of intracellular Ca2+ concentration ([Ca2+]i) in response to KCl was slowed and 73% corrected by taurine. The amplitudes of caffeine and ATP-induced [Ca2+]i transients were decreased by 47 and 27% (P < 0.05), respectively, in diabetic rat DRG sensory neurons and corrected by 74 and 93% (P < 0.05), respectively, by taurine replacement. These data indicate that taurine is important in the regulation of neuronal Ca2+ signaling and that taurine deficiency may predispose one to nerve hyperexcitability and pain, complicating diabetes.

Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

“…Here, the tail-flick response latency appeared decreased in rats with short-term STZ-induced diabetes, consistent with independent measurements of the paw-withdrawal time from noxious thermal stimuli, which, in contrast to the tail-flick test, included supraspinal sensory processing (23). Diabetic rats demonstrated reduced latencies of both responses, which is consistent with the presence of transient thermal hyperalgesia and is in line with our previous studies (13,30) and other reports (3,7,9). Both tail-flick and paw-withdrawal latencies were at least partially corrected by PARP inhibition, consistent with other findings (3,4,7) implicating oxidative-nitrosative stress as well as other mechanisms contributing to free radical and oxidant generation (e.g., increased aldose reductase [9] and protein kinase C [26] activities) to abnormal sensory responses to thermal noxious stimuli in diabetes.…”

“…Despite these limitations, assessment of behavioral responses to external stimuli in diabetic rodents provides valuable information regarding the mechanisms of abnormal sensation and pain associated with diabetes. Recent behavioral studies have demonstrated that 1) both diabetic rats and mice display altered thermal and mechanical algesia in response to noxious stimuli as well as tactile allodynia, although a type of response (i.e., hyper-or hypoalgesia) often depends on animal species and duration of diabetes (3,4,9,13) and 2) abnormal sensory responses are alleviated by protracted normoglycemia (23) and are amenable to at least some pathogenetic treatments (e.g., aldose reductase inhibitors [9], neurotrophic factors [9], the protein kinase C inhibitor LY333531 [26], rosuvastatin [27], and antioxidants [3,4,7,13]) that also reduce manifestations of large motor and sensory fiber neuropathy (1-5,26 -28). Our findings have shown that 1) PARP activation is implicated in hyperalgesia to noxious thermal, mechanical, and chemical stimuli and 2) PARP inhibitor treatment alleviates, but does not completely normalize, tail-flick and paw-withdrawal response latencies, mechanical and tactile withdrawal thresholds, and exaggerated flinching behavior in rats with short-term STZ-induced diabetes.…”

A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice

“…Numerous pharmacological studies in animal models have been performed to sort out the involvement of the key hyperglycemia-induced biochemical mechanisms in diabetesassociated changes in thermal nociception. Aldose reductase inhibitors (ARIs, Calcutt et al, 2004), antioxidants i.e., taurine (Li et al, 2005b), α-lipoic acid (Cameron et al, 2001a), the hydroxyl radical scavenger dimethylthiourea (Cameron et al, 2001b), as well as the protein kinase C inhibitor LY333531 (Cotter et al, 2002), the PARP inhibitor 1,5-isoqunolinediol and PARP inhibitor-containing combination therapies (Li et al, 2005a), have been found to prevent or correct thermal hyperalgesia in STZ-diabetic rats. Taurine prevented thermal hyperalgesia in ZDF rats (Li et al, 2006).…”

“…Another phenomenon, mechanical hyperalgesia, detected by reduced paw withdrawal thresholds during paw stimulation with rigid von Frey filaments or Randall-Sellito test, has been found clearly manifest in STZ-diabetic and ZDF rats (Cameron et al, 2001a,b;Cotter et al, 2002;Ilnytska et al, 2006;Li et al, 2006), and reversed or alleviated by antioxidants including α-lipoic acid (Cameron et al, 2001a), dimethylthiourea (Cameron et al, 2001b), taurine (Li et al, 2005b) as well as PARP inhibitors . Of interest, STZdiabetic mice develop mechanical hypo-, rather than hyperalgesia, i.e.…”

The Effect of Subacute Supplementation of Taurine on Spatial Learning and Memory

“…In these conflicting studies, the passive avoidance test was adopted to -Note-evaluate the effect of taurine. Because taurine was reported to change pain sensitivity [11,18], not only the passive avoidance test but also another kind of behavioral test needs to be applied.…”