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      Gabapentin reverses central pain sensitization following a collagenase-induced intrathalamic hemorrhage in rats


      Journal of Pain Research

      Dove Medical Press

      central pain, thalamus, amitriptyline, carbamazepine

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          The treatment of central neuropathic pain remains amongst the biggest challenges for pain specialists. The main objective of this study was to assess gabapentin (GBP), amitriptyline (AMI), and carbamazepine (CARBA) for the treatment of a rodent central neuropathic pain model.


          Male Sprague Dawley rats were trained on the rotarod, Hargreaves, Von Frey and acetone behavioral tests, and baseline values were obtained prior to surgery. A stereotaxic injection of either a collagenase solution or saline was made in the right ventral posterolateral thalamic nucleus. The rats were tested on days 2, 4, 8, and 11 postsurgery. They were retested at regular intervals from day 15 to day 25 postsurgery, after oral administration of either the vehicle (n=7 and n=8 rats with intracerebral injections of collagenase and saline, respectively) or the different drugs (GBP [60 mg/kg], AMI [10 mg/kg], CARBA [100 mg/kg]; n=8 rats/drug).


          A significant decrease in the mechanical thresholds and no change in heat threshold were observed in both hind limbs in the collagenase group, as we had previously shown elsewhere. Reversal of the mechanical hypersensitivity was achieved only with GBP ( P<0.05). AMI and CARBA, at the dosages used, failed to show any effect on mechanical thresholds. Transient cold allodynia was observed in some collagenase-injected rats but failed to be statistically significant.


          Intrathalamic hemorrhaging in the ventrolateral thalamic nucleus induced a bilateral mechanical allodynia, which was reversed by GBP but not AMI or CARBA.

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          Most cited references 39

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          A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.

          A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
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            Collagenase-induced intracerebral hemorrhage in rats.

            Intracranial bleeding is an important cause of brain masses and edema. To study the pathophysiology of intracerebral hemorrhage, we produced experimental hemorrhages in 53 rats and characterized the lesion by histology, brain water content, and behavior. Adult rats had 2 microliters saline containing 0.5 unit bacterial collagenase infused into the left caudate nucleus. Histologically, erythrocytes were seen around blood vessels at the needle puncture site within the first hour. By 4 hours there were hematomas, the size of which depended on the amount of collagenase injected. Necrotic masses containing fluid, blood cells, and fibrin were seen at 24 hours. Lipid-filled macrophages were observed at 7 days and cysts at 3 weeks. Water content was significantly increased 4, 24, and 48 hours after infusion at the needle puncture site and for 24 hours in posterior brain sections. Behavioral abnormalities were present for 48 hours, with recovery of function occurring during the first week. Brain tissue contains Type IV collagen in the basal lamina. Collagenase, which occurs in an inactive form in cells, is released and activated during injury, leading to disruption of the extracellular matrix. Collagenase-induced intracerebral hemorrhage is a reproducible animal model for the study of the effects of the hematoma and brain edema.
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              Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.

              Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                Dove Medical Press
                17 December 2013
                : 7
                : 5-12
                Faculty of Veterinary Medicine, Department of Veterinary Biomedicine, University of Montreal, Saint-Hyacinthe, QC, Canada
                Author notes
                Correspondence: Pascal Vachon, Université de Montréal, Faculté de Médecine Vétérinaire, Département de Biomédecine Vétérinaire, 3200 Sicotte, St-Hyacinthe, QC H2L 2M2, Canada, Tel +1 450 773 8521 ext 8294, Email pascal.vachon@ 123456umontreal.ca
                © 2014 Castel and Vachon. 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.

                Original Research

                Anesthesiology & Pain management

                central pain, amitriptyline, carbamazepine, thalamus


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