The Journal of Neurophysiology Vol. 81 No. 2 February 1999, pp. 455-466
Copyright ©1999 The American Physiological Society

Uninjured C-Fiber Nociceptors Develop Spontaneous Activity and -Adrenergic Sensitivity Following L₆ Spinal Nerve Ligation in Monkey

Z. Ali, M. Ringkamp, T. V. Hartke, H. F. Chien, N. A. Flavahan, J. N. Campbell, and R. A. Meyer

Johns Hopkins University, School of Medicine, Baltimore, Maryland 21218

Ali, Z., M. Ringkamp, T. V. Hartke, H. F. Chien, N. A. Flavahan, J. N. Campbell, and R. A. Meyer. Uninjured cutaneous C-fiber nociceptors develop spontaneous activity and -adrenergic sensitivity following L₆ spinal nerve ligation in the monkey. J. Neurophysiol. 81: 455-466, 1999. We investigated whether uninjured cutaneous C-fiber nociceptors in primates develop abnormal responses after partial denervation of the skin. Partial denervation was induced by tightly ligating spinal nerve L₆ that innervates the dorsum of the foot. Using an in vitro skin-nerve preparation, we recorded from uninjured single afferent nerve fibers in the superficial peroneal nerve. Recordings were made from 32 C-fiber nociceptors 2-3 wk after ligation and from 29 C-fiber nociceptors in control animals. Phenylephrine, a selective ₁-adrenergic agonist, and UK14304 (UK), a selective ₂-adrenergic agonist, were applied to the receptive field for 5 min in increasing concentrations from 0.1 to 100 µM. Nociceptors from in vitro control experiments were not significantly different from nociceptors recorded by us previously in in vivo experiments. In comparison to in vitro control animals, the afferents found in lesioned animals had 1) a significantly higher incidence of spontaneous activity, 2) a significantly higher incidence of response to phenylephrine, and 3) a higher incidence of response to UK. In lesioned animals, the peak response to phenylephrine was significantly greater than to UK, and the mechanical threshold of phenylephrine-sensitive afferents was significantly lower than for phenylephrine-insensitive afferents. Staining with protein gene product 9.5 revealed an ~55% reduction in the number of unmyelinated terminals in the epidermis of the lesioned limb compared with the contralateral limb. Thus uninjured cutaneous C-fiber nociceptors that innervate skin partially denervated by ligation of a spinal nerve acquire two abnormal properties: spontaneous activity and -adrenergic sensitivity. These abnormalities in nociceptor function may contribute to neuropathic pain.

This article has been cited by other articles:

				K. Orstavik, B. Namer, R. Schmidt, M. Schmelz, M. Hilliges, C. Weidner, R. W. Carr, H. Handwerker, E. Jorum, and H. E. Torebjork Abnormal Function of C-Fibers in Patients with Diabetic Neuropathy. J. Neurosci., November 1, 2006; 26(44): 11287 - 11294. [Abstract] [Full Text] [PDF]

				L. Djouhri, S. Koutsikou, X. Fang, S. McMullan, and S. N. Lawson Spontaneous Pain, Both Neuropathic and Inflammatory, Is Related to Frequency of Spontaneous Firing in Intact C-Fiber Nociceptors J. Neurosci., January 25, 2006; 26(4): 1281 - 1292. [Abstract] [Full Text] [PDF]

				B. Liu and J. C. Eisenach Hyperexcitability of Axotomized and Neighboring Unaxotomized Sensory Neurons Is Reduced Days After Perineural Clonidine at the Site of Injury J Neurophysiol, November 1, 2005; 94(5): 3159 - 3167. [Abstract] [Full Text] [PDF]

				K. Obata, H. Yamanaka, K. Kobayashi, Y. Dai, T. Mizushima, H. Katsura, T. Fukuoka, A. Tokunaga, and K. Noguchi Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation J. Neurosci., November 10, 2004; 24(45): 10211 - 10222. [Abstract] [Full Text] [PDF]

				R.-R. Ji and G. Strichartz Cell Signaling and the Genesis of Neuropathic Pain Sci. Signal., September 28, 2004; 2004(252): re14 - re14. [Abstract] [Full Text] [PDF]

				S. Zahn, S. Leis, C. Schick, M. Schmelz, and F. Birklein No {alpha}-adrenoreceptor-induced C-fiber activation in healthy human skin J Appl Physiol, April 1, 2004; 96(4): 1380 - 1384. [Abstract] [Full Text] [PDF]

				P. D. Drummond Involvement of the Sympathetic Nervous System in Complex Regional Pain Syndrome International Journal of Lower Extremity Wounds, March 1, 2004; 3(1): 35 - 42. [Abstract] [PDF]

				P D Drummond and P M Finch Persistence of pain induced by startle and forehead cooling after sympathetic blockade in patients with complex regional pain syndrome J. Neurol. Neurosurg. Psychiatry, January 1, 2004; 75(1): 98 - 102. [Abstract] [Full Text] [PDF]

				M. Schafers, D. H. Lee, D. Brors, T. L. Yaksh, and L. S. Sorkin Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-alpha after Spinal Nerve Ligation J. Neurosci., April 1, 2003; 23(7): 3028 - 3038. [Abstract] [Full Text] [PDF]

				C. Ma, Y. Shu, Z. Zheng, Y. Chen, H. Yao, K. W. Greenquist, F. A. White, and R. H. LaMotte Similar Electrophysiological Changes in Axotomized and Neighboring Intact Dorsal Root Ganglion Neurons J Neurophysiol, March 1, 2003; 89(3): 1588 - 1602. [Abstract] [Full Text] [PDF]

				Q. Lin, X. Zou, L. Fang, and W. D. Willis Sympathetic Modulation of Acute Cutaneous Flare Induced by Intradermal Injection of Capsaicin in Anesthetized Rats J Neurophysiol, February 1, 2003; 89(2): 853 - 861. [Abstract] [Full Text] [PDF]

				M. S. Gold, D. Weinreich, C.-S. Kim, R. Wang, J. Treanor, F. Porreca, and J. Lai Redistribution of NaV1.8 in Uninjured Axons Enables Neuropathic Pain J. Neurosci., January 1, 2003; 23(1): 158 - 166. [Abstract] [Full Text] [PDF]

				L. R. Watkins and S. F. Maier Beyond Neurons: Evidence That Immune and Glial Cells Contribute to Pathological Pain States Physiol Rev, October 1, 2002; 82(4): 981 - 1011. [Abstract] [Full Text] [PDF]

				G. Wu, M. Ringkamp, B. B. Murinson, E. M. Pogatzki, T. V. Hartke, H. M. Weerahandi, J. N. Campbell, J. W. Griffin, and R. A. Meyer Degeneration of Myelinated Efferent Fibers Induces Spontaneous Activity in Uninjured C-Fiber Afferents J. Neurosci., September 1, 2002; 22(17): 7746 - 7753. [Abstract] [Full Text] [PDF]

				E. M. Pogatzki, G. F. Gebhart, and T. J. Brennan Characterization of Adelta - and C-Fibers Innervating the Plantar Rat Hindpaw One Day After an Incision J Neurophysiol, February 1, 2002; 87(2): 721 - 731. [Abstract] [Full Text] [PDF]

				D. M. Cain, P. W. Wacnik, M. Turner, G. Wendelschafer-Crabb, W. R. Kennedy, G. L. Wilcox, and D. A. Simone Functional Interactions between Tumor and Peripheral Nerve: Changes in Excitability and Morphology of Primary Afferent Fibers in a Murine Model of Cancer Pain J. Neurosci., December 1, 2001; 21(23): 9367 - 9376. [Abstract] [Full Text] [PDF]

				P. D. Drummond, P. M. Finch, S. Skipworth, and P. Blockey Pain increases during sympathetic arousal in patients with complex regional pain syndrome Neurology, October 9, 2001; 57(7): 1296 - 1303. [Abstract] [Full Text] [PDF]

				M. KRESS and H. FICKENSCHER Infection by human varicella-zoster virus confers norepinephrine sensitivity to sensory neurons from rat dorsal root ganglia FASEB J, April 1, 2001; 15(6): 1037 - 1043. [Abstract] [Full Text] [PDF]

				J.-M. Zhang, H. Li, and S. J. Brull Perfusion of the Mechanically Compressed Lumbar Ganglion With Lidocaine Reduces Mechanical Hyperalgesia and Allodynia in the Rat J Neurophysiol, August 1, 2000; 84(2): 798 - 805. [Abstract] [Full Text] [PDF]

				X.-J. Song, S.-J. Hu, K. W. Greenquist, J.-M. Zhang, and R. H. LaMotte Mechanical and Thermal Hyperalgesia and Ectopic Neuronal Discharge After Chronic Compression of Dorsal Root Ganglia J Neurophysiol, December 1, 1999; 82(6): 3347 - 3358. [Abstract] [Full Text] [PDF]

				E. R. Perl Causalgia, pathological pain, and adrenergic receptors PNAS, July 6, 1999; 96(14): 7664 - 7667. [Abstract] [Full Text] [PDF]

				G. Wu, M. Ringkamp, T. V. Hartke, B. B. Murinson, J. N. Campbell, J. W. Griffin, and R. A. Meyer Early Onset of Spontaneous Activity in Uninjured C-Fiber Nociceptors after Injury to Neighboring Nerve Fibers J. Neurosci., April 15, 2001; 21(8): RC140 - RC140. [Abstract] [Full Text] [PDF]