Research reportLow dose of tetrodotoxin reduces neuropathic pain behaviors in an animal model
Introduction
In neuropathic pain conditions, spontaneous discharges generated from abnormal sites (ectopic discharges) by injured afferent neurons are considered to be a major input to the spinal cord, causing central sensitization and, thus, leading to chronic pain [14], [33]. The mechanisms for the generation of ectopic discharges are not clear. However, one mechanism that has been proposed involves the neuronal membrane becoming unstable due to the accumulation of sodium channels at the injury site [10], [25].
Functionally, there are two types of sodium currents which are mediated by multiple subtypes of sodium channels and classified based on their sensitivity to tetrodotoxin (TTX): TTX-sensitive (TTXs) and TTX-resistant (TTXr) [5], [13], [21], [30]. In normal adult dorsal root ganglion (DRG) neurons, TTXr sodium channels are expressed only in small neurons [2], [31], [34] that presumably transmit nociceptive inputs. Thus, TTXr sodium channels are believed to be important in the transmission of pain in normal animals. However, in abnormal conditions, such as after peripheral nerve injury, it is not clear which subtype of sodium channel is critically important for the maintenance of pain behaviors.
We hypothesize that the accumulation of TTXs sodium channels in the injured DRG neurons is a critically important component of ectopic discharge generation and, thus, the maintenance of mechanical allodynia in neuropathic animals. Using the L5 segmental spinal nerve ligation model of neuropathic pain, we tested this hypothesis by examining changes in the mechanical sensitivity of the affected hind paw after application of TTX to the L5 DRG.
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Materials and methods
Experiments were performed on 22 young adult, male, Sprague–Dawley rats (150–200 g, Harlan, Indianapolis). Animals were housed in groups of three in plastic cages with soft bedding and were provided with free access to food and water under a 12/12 h reversed light–dark cycle. All animals were acclimated for 7 days before the experiment.
With the animal under sodium pentobarbital anesthesia (Nembutal, 50 mg/kg, i.p.), the left L5 spinal nerve was tightly ligated with 6-0 silk thread [9], [18].
Results
All experimental animals appeared to be healthy throughout the entire experimental period, as evidenced by usual weight gain and normal grooming behaviors. The healthy general behaviors were maintained even when they received repeated injections (once every other day) of low doses of TTX (see below). After the L5 spinal nerve ligation, however, all rats showed a characteristic deformity of the foot, which included inversion of the foot and flexed toes [18], [27].
Normal rats did not actively
Discussion
The present study demonstrated that the topical application of a low dose of TTX to the DRG of the injured segment of the L5 spinal nerve significantly reduced allodynic behaviors in an animal model of neuropathic pain. It is well known that systemic or topical injection of lidocaine, a sodium channel blocker, reduces neuropathic pain in human patients [3], [4], [6] as well as neuropathic pain behaviors in animal models of neuropathic pain [1], [8]. These results suggest that sodium channels
Acknowledgements
This work was supported by NIH Grants NS 31680, NS 35057 and NS 11255. Y. S. L. was supported in part by the Sung San Foundation.
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