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      Effect of delayed intrathecal administration of capsaicin on neuropathic pain induced by chronic constriction injury of the sciatic nerve in rats

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          Abstract

          Purpose

          The current study was designed to examine the antinociceptive effect of intrathecally administered capsaicin, a transient receptor potential vanilloid 1 receptor agonist, in a rat model of neuropathic pain induced by unilateral sciatic nerve chronic constriction injury.

          Methods

          Male adult Sprague Dawley rats were randomly assigned to six groups, and all rats underwent unilateral sciatic nerve chronic constriction injury. Two weeks after injury, five groups received intrathecal administration of either capsaicin in three different dosing regimens or equal volumes of vehicle. The other group received intrathecal capsaicin on the third day after nerve injury. The antinociceptive effect of capsaicin was assessed by measuring the capsaicin-induced change in thermal and mechanical response thresholds.

          Results

          Capsaicin (150–300 μg/100–200 μL), when administered by fast infusion or chronic infusions at 8 μL/hour or 1 μL/hour, attenuated thermal hyperalgesia as indicated by significantly prolonging paw withdrawal latency to noxious thermal stimulation. The antinociceptive effect of capsaicin was more profound in the injured limb compared to that in the uninjured limb. When capsaicin was administered on the third day after nerve injury, it failed to attenuate thermal hyperalgesia. No significant effect on the mechanical response threshold was observed with intrathecally administered capsaicin.

          Conclusion

          Our data suggest that intrathecal capsaicin could significantly attenuate thermal hyperalgesia, depending on the time when the drug is given after nerve injury, and that the antinociceptive efficacy of intrathecal capsaicin positively correlates with the previously reported dynamic profile of spinal transient receptor potential vanilloid 1 activity after nerve injury.

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          Most cited references 15

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          A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.

           Gary Bennett,  Y. Xie (1988)
          A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.
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            VR1 protein expression increases in undamaged DRG neurons after partial nerve injury.

            Changes in phenotype or connectivity of primary afferent neurons following peripheral nerve injury may contribute to the hyperalgesia and allodynia associated with neuropathic pain conditions. Although earlier studies using partial nerve injury models have focused on the role of damaged fibres in the generation of ectopic discharges and pain, it is now thought that remaining undamaged fibres may be equally important. We have examined the expression of the sensory neuron-specific cation channel Vanilloid Receptor 1 (VR1), an important transducer of noxious stimuli, in three models of nerve injury in the rat, using anatomical separation or fluorescent retrograde tracers to identify damaged or undamaged sensory neurons. After total or partial sciatic nerve transection, or spinal nerve ligation, VR1-immunoreactivity (IR) was significantly reduced in the somata of all damaged dorsal root ganglion (DRG) neuronal profiles, compared to controls. However, after partial transection or spinal nerve ligation, VR1 expression was greater in the undamaged DRG somata than in controls. Unexpectedly, after L5 spinal nerve ligation, VR1-IR of the A-fibre somata increased approximately 3-fold in the uninjured L4 DRG compared to controls; a much greater increase than seen in the somata with C-fibres. Furthermore, we found that VR1-IR persisted in the transected sciatic nerve proximal to the lesion, despite its down-regulation in the damaged neuronal somata. This persistence in the nerve proximal to the lesion after nerve section, together with increased VR1 in DRG neurons left undamaged after partial nerve injury, may be crucial to the development or maintenance of neuropathic pain.
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              Lumbar catheterization of the spinal subarachnoid space in the rat.

              The method commonly used for catheterization of the lumbar subarachnoid space in the rat implies inserting the catheter through the atlanto-occipital (A-O) membrane and moving the catheter caudally along the spinal cord. The method is associated with a considerable morbidity. A method for direct catheterization of the lumbar subarachnoid space was therefore developed. Major surgery was avoided by using a catheter-through-needle technique. Of 32 rats, none died. There were no signs of neurological disturbances, and all animals gained weight as normal the first week after implantation. Data from rats catheterized by the A-O method were used for comparison. Of 40 animals, 2 died, 11 showed signs of neurological disturbances, and the mean weight was reduced during the first week after catheterization. The two groups of animals showed different behavioural responses to intrathecal injection of N-methyl-D-aspartate (NMDA, 0.1-1.6 mM, 15 microliters) which is thought to stimulate afferent pathways mediating nociception. Animals with a lumbar catheter showed licking, biting and scratching behaviour in a dose-related manner for concentrations up to 1.6 mM. The animals with A-O catheters showed a maximum level of this behaviour already at 0.4 mM, while 0.5 mM induced convulsions. A possible explanation of this difference in response to NMDA could be a long-lasting pain state in the A-O group, caused by catheter-induced changes in the spinal cord and by the extensive surgery. It is concluded that the direct lumbar catheterization has several advantages compared to the A-O method, decreasing the suffering of the animals, the neurological disturbances and the interference with nociceptive functions of the spinal cord.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2014
                11 September 2014
                : 7
                : 547-554
                Affiliations
                [1 ]Department of Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
                [2 ]Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
                Author notes
                Correspondence: Maxim S Eckmann, Department of Anesthesiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA, Tel +1 210 450 9850, Fax +1 210 450 6095, Email eckmann@ 123456uthscsa.edu
                Article
                jpr-7-547
                10.2147/JPR.S66956
                4166214
                © 2014 Zhang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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