Journal of Molecular Neuroscience

, Volume 32, Issue 3, pp 228–234

Effect of Gabapentin on c-Fos Expression in the CNS after Paw Surgery in Rats



Gabapentin (neurontin), a GABA analogue anticonvulsant has proven to be effective in anti-nociceptive activity as well as for the treatment of anxiety. Gabapentin (GBP) is well tolerated and shows very favorable side effects profile: The exact molecular mechanism of action of GBP to block postoperative pain and stress is not known. Therefore, to identify the functional neuroanatomical target sites of GBP in post-surgery as well as its effect on postsurgical process, we examined the effects of GBP on c-Fos expression in the supraspinal part of the central nervous system in rats. Using a well-validated rat model of surgical pain, we studied the neuroanatomical functional target sites of gabapentin after paw surgery. The effect of GBP was examined by means of c-Fos immunohistochemistry. A single intraperitoneal injection (i.p.) of GBP (150 mg/kg) or saline (control) was administered 20 min before surgical incision in the paw under anesthesia. Ninety minutes after surgical incision, the deeply anesthetized rats were perfused transcardially with 4% paraformaldehyde. Serial 40-μm-thick sections of whole brain (except spinal cord) were cut and processed by immunohistochemistry to locate and quantify the sites and number of neurons with c-Fos immunoreactivity. Detection of c-Fos protein was performed using the peroxidase–antiperoxidase detection protocol. Our present study demonstrated that compared to control, administration of GBP (150 mg/kg, i.p.) before paw surgery significantly (p < 0.01) attenuated the incision-induced c-Fos expression only in the paraventricular nucleus of the hypothalamus. In addition, GBP-induced increase in c-Fos expression was observed in the dorsal raphe (DRN) and in the nucleus raphe magnus. Present results indicate that GBP may differentially modulate c-Fos expression in surgical paw incision. Moreover, this study provides some clue to examine whether GBP exerts its action simultaneously through two separate pathways in post-surgery.


c-Fos Gabapentin Paw incision Surgical stress Pain CNS Immunohistochemistry 


  1. Abe, M., Kurihara, T., Han, W., Shinomiya, K., & Tanabe, T. (2002). Changes in expression of voltage-dependent ion channel subunits in dorsal root ganglia of rats with radicular injury and pain. Spine, 27, 1517–1524.PubMedCrossRefGoogle Scholar
  2. Brennan, T. J. (2002). Frontiers in translational research: The etiology of incisional and postoperative pain. Anesthesiology, 97, 535–537.PubMedCrossRefGoogle Scholar
  3. Brennan, T. J., Vandermeulen, E. P., & Gebhart, G. F. (1996) Characterization of a rat model of incisional pain. Pain, 64, 493–501.PubMedCrossRefGoogle Scholar
  4. Brennan, T. J., Zahn, P. K., & Pogatzki-Zahn, E. M. (2005). Mechanisms of incisional pain. Anesthesiology Clinics of North America, 23, 1–20.PubMedCrossRefGoogle Scholar
  5. Chaouloff, F., Berton, O., & Mormede, P. (1999). Serotonin and stress. Neuropsychopharmacology, 21(2), 28S–32S.PubMedCrossRefGoogle Scholar
  6. Chauvin, M. (1999). Relieving post-operative pain. Presse Medicale, 28, 203–211.Google Scholar
  7. de Medeiros, M. A., Carlos Reis, L., & Eugenio, M. L. (2005). Stress-induced c-Fos expression is differentially modulated by dexamethasone, diazepam and imipramine. Neuropsychopharmacology, 30, 1246–1256.PubMedGoogle Scholar
  8. Dirks, J., Fredensborg, B. B., Christensen, D., Fomsgaard, J. S., Flyger, H., & Dahl, J. B. (2002) A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology, 97, 560–564.PubMedCrossRefGoogle Scholar
  9. Fassoulaki, A., Patris, K., Sarantopoulos, C., & Hogan, Q. (2002). The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesthesia and Analgesia, 95, 985–991.PubMedCrossRefGoogle Scholar
  10. Field, M. J., Holloman, E. F., McCleary, S., Hughes, J., & Singh, L. (1997a). Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. Journal of Pharmacology and Experimental Therapeutics, 282, 1242–1246.PubMedGoogle Scholar
  11. Field, M. J., Oles, R. J., Lewis, A. S., McCleary, S., Hughes, J., & Singh, L. (1997b). Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents. British Journal of Pharmacology, 121, 1513–1522.PubMedCrossRefGoogle Scholar
  12. Fujioka, T., Fujioka, A., Endoh, H., Sakata, Y., Furukawa, S., & Nakamura, S. (2003). Materno-fetal coordination of stress-induced Fos expression in the hypothalamic paraventricular nucleus during pregnancy. Neuroscience, 118, 409–415.PubMedCrossRefGoogle Scholar
  13. Gee, N. S., Brown, J. P., Dissanayake, V. U., & Offord, J. (1996). The novel anticonvulsant drug, gabapentin (neurontin), binds to the alpha2delta subunit of a calcium channel. Journal of Biological Chemistry, 271, 5768–5776.PubMedCrossRefGoogle Scholar
  14. Gilron, I. (2002). Is gabapentin a “broad-spectrum” analgesic? Anesthesiology, 97, 537–539.PubMedCrossRefGoogle Scholar
  15. Gilron, I., Biederman, J., Jhamandas, K., & Hong, M. (2003). Gabapentin blocks and reverses antinociceptive morphine tolerance in the rat paw-pressure and tail-flick tests. Anesthesiology, 98, 1288–1292.PubMedCrossRefGoogle Scholar
  16. Hirakawa, M., & Kawata, M. (1993). Distribution pattern of c-Fos expression induced by sciatic nerve sectioning in the rat central nervous system. Journal fur Hirnforschung, 34, 431–434.PubMedGoogle Scholar
  17. Holte, K., & Kehlet, H. (2002). Epidural anaesthesia and analgesica—effects on surgical stress responses and implications for postoperative nutrition. Clinical Nutrition, 21, 199–206.PubMedCrossRefGoogle Scholar
  18. Hughes, P., & Dragunow, M. (1995). Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. Pharmacological Reviews, 47, 133–178.PubMedGoogle Scholar
  19. Hwang, J. H., & Yaksh, T. L. (1997). Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat. Regional Anesthesia, 22, 249–256.PubMedCrossRefGoogle Scholar
  20. Inase, M., Nakahama, H., Otsjik, T., & Fang, J. (1987). Analgesic effects of serotonin microinjection into nucleus raphe magnus and nucleus raphe dorsalis evaluated by monosodium urate (MSU) tonic pain model in the rat. Brain Research, 426, 205–211.PubMedCrossRefGoogle Scholar
  21. Jones, S. L., & Light, A. R. (1990). Termination patterns of serotoninergic medullary raphe spinal fibers in rat lumbar spinal cord: An anterograde immunohistochemical study. Journal of Comparative Neurology, 297, 267–282.PubMedCrossRefGoogle Scholar
  22. Kaneko, M., Mestre, C., Sanchez, E. H., & Hammond, D. L. (2000). Intrathecally administered gabapentin inhibits formalin-evoked nociception and the expression of Fos-like immunoreactivity in the spinal cord of the rat. Journal of Pharmacology and Experimental Therapeutics, 292, 743–751.PubMedGoogle Scholar
  23. Kazi, J. A., Mori, S., Gao, H. Z., Uehara, F., & Nakagawa, S. (2002). Effect of enucleation on the expression of c-Fos protein in the supraoptic nucleus of the Japanese monkey (Macaca fuscata). Brain Research, 952, 331–334.PubMedCrossRefGoogle Scholar
  24. Menigaux, C., Adam, F., Guignard, B., Sessler, D. I., & Chauvin, M. (2005). Preoperative gabapentin decreases anxiety and improves early functional recovery from knee surgery. Anesthesia and Analgesia, 100, 1394–1399.PubMedCrossRefGoogle Scholar
  25. Moiniche, S., Kehlet, H., & Dahl, J. B. (2002). A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: The role of timing of analgesia. Anesthesiology, 96, 725–741.PubMedCrossRefGoogle Scholar
  26. Pandey, C. K., Sahay, S., Gupta, D., Ambesh, S. P., Singh, R. B., Raza, M. et al. (2004). Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy. Canadian Journal of Anesthesia, 51, 986–989.PubMedCrossRefGoogle Scholar
  27. Patel, M. K., Gonzalez, M. I., Bramwell, S., Pinnock, R. D., & Lee, K. (2000). Gabapentin inhibits excitatory synaptic transmission in the hyperalgesic spinal cord. British Journal of Pharmacology, 130, 1731–1734.PubMedCrossRefGoogle Scholar
  28. Pollack, M. H., Matthews, J., & Scott, E. L. (1998). Gabapentin as a potential treatment for anxiety disorders. American Journal of Psychiatry, 155, 992–993.PubMedGoogle Scholar
  29. Rao, M. L., Clarenbach, P., Vahlensieck, M., & Kratzschmar, S. (1988). Gabapentin augments whole blood serotonin in healthy young men. Journal of Neural Transmission, 73, 129–134.PubMedCrossRefGoogle Scholar
  30. Senba, E., & Ueyama, T. (1997). Stress-induced expression of immediate early genes in the brain and peripheral organs of the rat. Neuroscience Research, 29, 183–207.PubMedCrossRefGoogle Scholar
  31. Shu, S. Y., Ju, G., & Fan, L. Z. (1988). The glucose oxidase–DAB–nickel method in peroxidase histochemistry of the nervous system. Neuroscience Letters, 85, 169–171.PubMedCrossRefGoogle Scholar
  32. Solomon, R. E., & Gebhart, G. F. (1988). Mechanisms of effects of intrathecal serotonin on nociception and blood pressure in rats. Journal of Pharmacology and Experimental Therapeutics, 245, 905–912.PubMedGoogle Scholar
  33. Stenberg, C., Ovlisen, K., Svendsen, O., & Lauritzen, B. (2005). Effect of local anaesthesia on neuronal c-fos expression in the spinal dorsal horn and hypothalamic paraventricular nucleus after surgery in rats. Basic Clinical Pharmacology and Toxicology, 96, 381–386.CrossRefGoogle Scholar
  34. Struder, H. K., & Weicker, H. (2001a). Physiology and pathophysiology of the serotonergic system and its implications on mental and physical performance, Part I. International Journal of Sports Medicine, 22, 467–481.PubMedCrossRefGoogle Scholar
  35. Struder, H. K., & Weicker, H. (2001b). Physiology and pathophysiology of the serotonergic system and its implications on mental and physical performance, Part II. International Journal of Sports Medicine, 22, 482–497.PubMedCrossRefGoogle Scholar
  36. Suzuki, R., Rahman, W., Rygh, L. J., Webber, M., Hunt, S. P., & Dickenson, A. H. (2005). Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin. Pain, 117, 292–303.PubMedCrossRefGoogle Scholar
  37. Svendsen, O., & Lykkegaard, K. (2000). Neuronal c-Fos immunoreactivity as a quantitative measure of stress or pain. Acta Agriculturae Scandinavica, Section A, Animal Science Supplementum, 30, 131–134.Google Scholar
  38. Swanson, L. W., & Sawchenko, P. E. (1980). Paraventricular nucleus: A site for the integration of neuroendocrine and autonomic mechanisms. Neuroendocrinology, 31, 410–417.PubMedGoogle Scholar
  39. Tanabe, M., Takasu, K., Kasuya, N., Shimizu, S., Honda, M., & Ono, H. (2005). Role of descending noradrenergic system and spinal alpha2-adrenergic receptors in the effects of gabapentin on thermal and mechanical nociception after partial nerve injury in the mouse. British Journal of Pharmacology, 144, 703–714.PubMedCrossRefGoogle Scholar
  40. Yaksh, T. L., & Wilson, P. R. (1979). Spinal serotonin terminal system mediates antinociception. Journal of Pharmacology and Experimental Therapeutics, 208, 446–453.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of Anaesthesia, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

Personalised recommendations