- Email: [email protected]
Development of inflammatory hypersensitivity and augmentation of sodium channels in rat dorsal root ganglia
Brain Research 824 Ž1999. 296–299
Short communication
Development of inflammatory hypersensitivity and augmentation of sodium channels in rat dorsal root ganglia H.J. Gould III a
a, )
, T.N. Gould a , D. Paul a , J.D. England a , Z.P. Liu a , S.C. Reeb a , S.R. Levinson
b
Department of Neurology, Louisiana State UniÕersity Medical Center, 1542 Tulane AÕenue, New Orleans, LA 70112, USA b Department of Physiology, UniÕersity of Colorado School of Medicine, DenÕer, CO, USA Accepted 2 February 1999
Abstract The development of thermal allodynia in relationship to sodium channel augmentation in dorsal root ganglia ŽDRGs. was studied in albino rats. Paw withdrawal latencies were measured hourly following complete Freund’s adjuvant ŽCFA. injections. Sodium channels were demonstrated with immunocytochemistry. Sustained minimum latencies were attained between 10 and 12 h post-injection. Sodium channel labeling began to increase at 23 h post-injection and reached maximum levels by 24 h. Thermal hypersensitivity is thus established 12 h before sodium channel augmentation can be demonstrated. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Sodium channel augmentation; Inflammation; Pain; Dorsal root ganglia
The enhanced expression of sodium channels has been proposed to underlie the hypersensitivity of peripheral neurons as a result of injury w3–5,9,14,15,20x. We have observed in addition that in apparent correlation with the onset of thermal allodynia, sodium channel expression within dorsal root ganglia ŽDRGs. is dramatically enhanced within 24 h of a subcutaneous injection of complete Freund’s adjuvant ŽCFA. and that the augmentation of sodium channel production is maintained beyond the resolution of the hyperalgesic state for at least 2 months post-injection w10x. Since sodium channels have been associated with hyperalgesia and hyperexcitability and may provide a foundation for the maintenance of repetitive neuronal firing in chronic pain states w3,6–8,14,15,18,20x, it is important to examine the early events related to sodium channel augmentation. The latency to paw withdrawal was the determinant of pain threshold and was measured according to the protocol of Hargreaves et al. w13x. Two groups of eight Sprague– Dawley rats weighing between 250 and 350 g were placed in Plexiglass chambers on a glass plate and were allowed free range of activity within the chamber. The glabrous surface of each hindpaw was stimulated through the glass
) Corresponding [email protected]
author.
Fax:
q 1-504-568-7130;
E-mail:
plate using a halogen heat source. The latency of paw withdrawal from the onset of stimulation was measured using an IITC analgesiometer ŽIITC Life Science, Woodland Hills, CA.. The stimulus was automatically discontinued after 10.7 s to avoid tissue damage. Baseline pain thresholds were determined in two separate testing sessions 1 h apart, beginning 2 h before subcutaneous CFA injection. One hindpaw of each animal was injected with either 0.1 ml of CFA Ž Mycobacterium tuberculosis; Sigma. or an equal volume of normal saline. The hindlimb contralateral to the injected paw provided an internal control. Withdrawal thresholds were measured immediately following injection and then hourly for 24 h. For sodium channel immunocytochemistry, pairs of rats that had undergone behavioral testing were perfused immediately after the last testing session. A separate group of rats was anesthetized with a combination of ketamine Ž60 mgrkg. and xylazine Ž8 mgrkg.. One hindpaw of each rat received a 0.5-ml subcutaneous injection of CFA. The rats were perfused transcardially at selected hourly intervals between 4 and 24 h after injection with 0.9% saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.6. The L 4 –S 1 DRGs and portions of the sciatic and medial plantar nerves were dissected from each animal and cut into 10–30 mm thick sections in a cryostat. Sections were processed according to procedures previously described w10x. The slides were
0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 1 2 1 8 - 4
H.J. Gould III et al.r Brain Research 824 (1999) 296–299
viewed with a Leica laser confocal ŽCLSM-MVNE-147. microscope. Fig. 1 shows that withdrawal latencies in the injected paw immediately following the CFA injection, were reduced to approximately 2.5 s. Over the next 3 h the latencies returned to control levels. Between hours 3 and 8 post-injection, paw withdrawal latencies decreased steadily to approximately 2 s and remained between 2 and 3 s for the balance of behavioral testing. In our earlier studies, control paw withdrawal thresholds that were tested at intervals of 24 h or greater remained unchanged from baseline. In contrast, the contralateral-control, the salineinjected control, and the untreated-control paws when tested hourly in the present study demonstrated a gradual decline in the withdrawal latencies from baseline values to approximately 4.5 s. This response is consistent with the development of a centrally mediated, conditioned avoidance response rather than with the development of hyperalgesia w1,19x. Sodium channel labeling was not observed above control levels ŽFig. 2A. in DRGs associated with the hindpaws injected with 0.5 ml of CFA until 23 h post-injection. Comparing Fig. 2A and B shows that at 23 h post-injection, there is a significant increase in sodium channel labeling in DRGs associated with the CFA-injected paw. Maximum sodium channel labeling is observed in neurons
297
of all sizes at 24 h post-injection ŽFig. 2C.. Fewer neurons were labeled after the 0.1-ml injections of CFA than after 0.5 ml injections but the intensity of the labeling, the cell size distribution, and the intracellular distribution of the label was similar to that seen following 0.5 ml injections. Only background labeling was observed in DRGs associated with the contralateral-control, the saline-injected control, and the untreated-control paws. There was no apparent difference in sodium channel labeling of DRGs associated with control paws that responded with decreased latencies to hourly thermal stimulation when compared to DRGs associated with unstimulated, i.e., baseline, control paws. The functional significance of sodium channel modulation in chronic pain states is yet to be determined. Clearly, sodium channels are thought to play a role in neuronal excitability especially in neuropathic states w2,4,5x. In inflammation, however, the role of sodium channels is less well established. Indeed, the lack of a clinical analgesic response to typical systemic sodium channel blockade in states of inflammation w11x suggests that sodium channels play a minimal role in inflammatory allodynia. Our recent studies w10x, however, have shown that a CFA-induced state of inflammation dramatically enhances sodium channel production and that the changes in sodium channel production are rapid and prolonged. The present study
Fig. 1. Changes in paw withdrawal latencies within 24 h of CFA injection. Reductions in the withdrawal latency are seen immediately after CFA injection. Latencies recover to baseline levels within 3 h of injection then progressively decline to maximum effect by 12 h post-injection. Saline-injected and contralateral-control paw withdrawal latencies show a steady decline with repetitive stimulation but do not achieve levels of sensitivity seen in the injected paw.
298
H.J. Gould III et al.r Brain Research 824 (1999) 296–299
Fig. 2. Development of sodium channel labeling in dorsal root ganglia following CFA injection. A contralateral, uninjected-control ganglion as seen with the confocal microscope is depicted in panel ŽA.. The photomicrograph depicts background labeling that is identical to that seen in ganglia associated with hindpaws injected with normal saline at anytime post-injection or with CFA at anytime prior to 23 h post-injection. Sodium channel labeling seen in DRGs ipsilateral to a CFA-injected hindpaw at 23 and 24 h post-injection are depicted in ŽB. and ŽC., respectively. The punctate labeling is thought to reflect increased levels of sodium channel protein in within vesicles of the trans-Golgi network. The ganglion depicted in D was pre-blocked with purified sodium channel following CFA injection into the ipsilateral hindpaw 24 h before perfusion. Calibration bar s 20 mm.
extends these observations and shows that sodium channel augmentation in neurons of all sizes within DRGs begins at 23 h post-injection, approximately 12 h after the development of a prolonged state of allodynia. Furthermore, the number of neurons that demonstrate sodium channel augmentation appears to be proportional to the size of the inducing inflammatory lesion. Although there is a temporal relationship between the development of thermal allodynia
and the augmentation of sodium channel production, a causal relationship between these events is not clear. It is notable, however, that the enhanced sodium channel production is transient in large DRG cells most typically related to populations of large myelinated, Ab and Ad, axons, but only persists in this neuronal population for approximately 2 weeks during the period of thermal allodynia w10x. These results suggest that sodium channel
H.J. Gould III et al.r Brain Research 824 (1999) 296–299
augmentation in the large myelinated neurons may be responsible for the maintenance of the acute phase of inflammatory allodynia perhaps through enhancement of repetitive neuronal activity and the facilitation of the mechanisms of central sensitization. In contrast, augmented sodium channel production persists beyond the period of thermal allodynia in small DRG neurons thought to be related to the unmyelinated, nociceptive C-fibers. It is possible that the persistence of sodium channels in the population of small neurons, rather than maintaining an allodynic state, provides the substrate for the maintenance of spontaneous neuronal activity in DRGs and thus the basis for wound vigilance. The increased sodium channel density in the small neurons alternatively may be more specifically associated with the states of mechanical w16,17x or chemical w12x allodynia that we have not examined.
w7x
w8x
w9x
w10x
w11x
w12x
Acknowledgements HJG and JDE are supported by US Army Medical Research Grant ŽDAMD17-93-V-3013., DP is supported by NIDA Grant ŽDA07379., and SRL is supported by NIH Grant ŽNS34375..
w13x
w14x
w15x
References w1x C. Astrup, Pavlovian Psychiatry—A New Synthesis, Charles C. Thomas, Springfield, IL, 1965. w2x J.N. Campbell, S.N. Raja, R.A. Meyer, S.E. MacKinnon, Myelinated afferents signal the hyperalgesia associated with nerve injury, Pain 32 Ž1988. 89–94. w3x T.R. Cummins, S.G. Waxman, Down-regulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury, J. Neurosci. 17 Ž1997. 3503–3514. w4x M. Devor, The pathophysiology of damaged peripheral nerves, in: P.D. Wall, R. Melzack ŽEds.., Textbook of Pain, Vol. 3, Livingstone, Edinburgh, 1994, pp. 79–100. w5x M. Devor, P. Lomazov, O. Matzner, Sodium channel accumulation in injured axons as a substrate for neuropathic pain, in: J. Boivie, P. Hansson, U. Lindblom ŽEds.., Touch, Temperature, and Pain in Health and Disease: Mechanisms and Assessments, Progress in Pain Research and Management, Vol. 3, IASP Press, Seattle, 1994, pp. 207–230. w6x S.D. Dib-Hajj, J.A. Black, T.R. Cummins, A.M. Kenney, J.D.
w16x
w17x
w18x
w19x
w20x
299
Kocsis, S.G. Waxman, Rescue of a-SNS sodium channel expression in small dorsal root ganglion neurons after axotomy by nerve growth factor in vivo, J. Neurophysiol. 79 Ž1998. 2668–2676. S. Dib-Hajj, J.A. Black, P. Felts, S.G. Waxman, Down-regulation of transcripts for Na channel a-SNS in spinal sensory neurons following axotomy, Proc. Natl. Acad. Sci. USA 93 Ž1996. 14950–14954. S.D. Dib-Hajj, L. Tyrrell, J.A. Black, S.G. Waxman, NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy, Proc. Natl. Acad. Sci. USA 95 Ž1998. . J.D. England, F. Gamboni, M.A. Ferguson, S.R. Levinson, Sodium channels accumulate at the tips of injured axons, Muscle and Nerve 17 Ž1994. 593–598. H.J. Gould III, J.D. England, Z.P. Liu, S.R. Levinson, Rapid sodium channel augmentation in response to inflammation induced by complete Freund’s adjuvant, Brain Res. 802 Ž1998. 69–74. H.J. Gould III, T.N. Gould, S.C. Reeb, D. Paul, The effect of gabapentin on inflammatory pain in rats, Analgesia 3 Ž1997. 131– 139. H.O. Handwerker, Pain producing substances, in: H.W. Kosterlitz, L.Y. Terenius ŽEds.., Pain and Society, Verlag Chemi, Weinheim, 1980, pp. 325–338. K. Hargreaves, R. Dubner, R. Brown, C. Flores, J. Joris, A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia, Pain 32 Ž1988. 77–88. S.D. Novakovic, E. Tzoumaka, J.G. McGivern, M. Haraguchi, L. Sangameswaran, K.R. Gogas, R.M. Eglen, J.C. Hunter, Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions, J. Neurosci. 18 Ž1998. 2174–2187. M.A. Rizzo, J.D. Kocsis, S.G. Waxman, Mechanisms of paraesthesiae, dysaesthesiae, and hyperaesthesiae: role of Naq channel heterogeneity, Eur. Neurol. 36 Ž1996. 3–12. A. Rueff, A.J.L.R. Dawson, L.M. Mendell, Characteristics of nerve growth factor induced hyperalgesia in adult rats: dependence on enhanced bradykinin-1 receptor activity but not neurokinin-1 receptor activation, Pain 66 Ž1996. 359–372. B. Safieh-Garabedian, S. Poole, A. Allchorne, J. Winter, C.J. Woolf, Contribution of interleukin-1b to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia, Br. J. Pharmacol. 115 Ž1995. 1265–1275. M. Tanaka, T.R. Cummins, K. Ishikawa, S.D. Dib-Hajj, J.A. Black, S.G. Waxman, SNS Naq channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model, NeuroReport 9 Ž1998. 967–972. R.F. Thompson, W.A. Spencer, Habituation: a model phenomenon for the study of neuronal substrates of behavior, Psychol. Rev. 73 Ž1966. 16–43. S.G. Waxman, J.D. Kocsis, J.A. Black, Type III sodium channel mRNA is expressed in embryonic, but not adult spinal sensory neurons and is reexpressed following axotomy, J. Neurophysiol. 72 Ž1994. 466–470.
Short communication
Development of inflammatory hypersensitivity and augmentation of sodium channels in rat dorsal root ganglia H.J. Gould III a
a, )
, T.N. Gould a , D. Paul a , J.D. England a , Z.P. Liu a , S.C. Reeb a , S.R. Levinson
b
Department of Neurology, Louisiana State UniÕersity Medical Center, 1542 Tulane AÕenue, New Orleans, LA 70112, USA b Department of Physiology, UniÕersity of Colorado School of Medicine, DenÕer, CO, USA Accepted 2 February 1999
Abstract The development of thermal allodynia in relationship to sodium channel augmentation in dorsal root ganglia ŽDRGs. was studied in albino rats. Paw withdrawal latencies were measured hourly following complete Freund’s adjuvant ŽCFA. injections. Sodium channels were demonstrated with immunocytochemistry. Sustained minimum latencies were attained between 10 and 12 h post-injection. Sodium channel labeling began to increase at 23 h post-injection and reached maximum levels by 24 h. Thermal hypersensitivity is thus established 12 h before sodium channel augmentation can be demonstrated. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Sodium channel augmentation; Inflammation; Pain; Dorsal root ganglia
The enhanced expression of sodium channels has been proposed to underlie the hypersensitivity of peripheral neurons as a result of injury w3–5,9,14,15,20x. We have observed in addition that in apparent correlation with the onset of thermal allodynia, sodium channel expression within dorsal root ganglia ŽDRGs. is dramatically enhanced within 24 h of a subcutaneous injection of complete Freund’s adjuvant ŽCFA. and that the augmentation of sodium channel production is maintained beyond the resolution of the hyperalgesic state for at least 2 months post-injection w10x. Since sodium channels have been associated with hyperalgesia and hyperexcitability and may provide a foundation for the maintenance of repetitive neuronal firing in chronic pain states w3,6–8,14,15,18,20x, it is important to examine the early events related to sodium channel augmentation. The latency to paw withdrawal was the determinant of pain threshold and was measured according to the protocol of Hargreaves et al. w13x. Two groups of eight Sprague– Dawley rats weighing between 250 and 350 g were placed in Plexiglass chambers on a glass plate and were allowed free range of activity within the chamber. The glabrous surface of each hindpaw was stimulated through the glass
) Corresponding [email protected]
author.
Fax:
q 1-504-568-7130;
E-mail:
plate using a halogen heat source. The latency of paw withdrawal from the onset of stimulation was measured using an IITC analgesiometer ŽIITC Life Science, Woodland Hills, CA.. The stimulus was automatically discontinued after 10.7 s to avoid tissue damage. Baseline pain thresholds were determined in two separate testing sessions 1 h apart, beginning 2 h before subcutaneous CFA injection. One hindpaw of each animal was injected with either 0.1 ml of CFA Ž Mycobacterium tuberculosis; Sigma. or an equal volume of normal saline. The hindlimb contralateral to the injected paw provided an internal control. Withdrawal thresholds were measured immediately following injection and then hourly for 24 h. For sodium channel immunocytochemistry, pairs of rats that had undergone behavioral testing were perfused immediately after the last testing session. A separate group of rats was anesthetized with a combination of ketamine Ž60 mgrkg. and xylazine Ž8 mgrkg.. One hindpaw of each rat received a 0.5-ml subcutaneous injection of CFA. The rats were perfused transcardially at selected hourly intervals between 4 and 24 h after injection with 0.9% saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.6. The L 4 –S 1 DRGs and portions of the sciatic and medial plantar nerves were dissected from each animal and cut into 10–30 mm thick sections in a cryostat. Sections were processed according to procedures previously described w10x. The slides were
0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 1 2 1 8 - 4
H.J. Gould III et al.r Brain Research 824 (1999) 296–299
viewed with a Leica laser confocal ŽCLSM-MVNE-147. microscope. Fig. 1 shows that withdrawal latencies in the injected paw immediately following the CFA injection, were reduced to approximately 2.5 s. Over the next 3 h the latencies returned to control levels. Between hours 3 and 8 post-injection, paw withdrawal latencies decreased steadily to approximately 2 s and remained between 2 and 3 s for the balance of behavioral testing. In our earlier studies, control paw withdrawal thresholds that were tested at intervals of 24 h or greater remained unchanged from baseline. In contrast, the contralateral-control, the salineinjected control, and the untreated-control paws when tested hourly in the present study demonstrated a gradual decline in the withdrawal latencies from baseline values to approximately 4.5 s. This response is consistent with the development of a centrally mediated, conditioned avoidance response rather than with the development of hyperalgesia w1,19x. Sodium channel labeling was not observed above control levels ŽFig. 2A. in DRGs associated with the hindpaws injected with 0.5 ml of CFA until 23 h post-injection. Comparing Fig. 2A and B shows that at 23 h post-injection, there is a significant increase in sodium channel labeling in DRGs associated with the CFA-injected paw. Maximum sodium channel labeling is observed in neurons
297
of all sizes at 24 h post-injection ŽFig. 2C.. Fewer neurons were labeled after the 0.1-ml injections of CFA than after 0.5 ml injections but the intensity of the labeling, the cell size distribution, and the intracellular distribution of the label was similar to that seen following 0.5 ml injections. Only background labeling was observed in DRGs associated with the contralateral-control, the saline-injected control, and the untreated-control paws. There was no apparent difference in sodium channel labeling of DRGs associated with control paws that responded with decreased latencies to hourly thermal stimulation when compared to DRGs associated with unstimulated, i.e., baseline, control paws. The functional significance of sodium channel modulation in chronic pain states is yet to be determined. Clearly, sodium channels are thought to play a role in neuronal excitability especially in neuropathic states w2,4,5x. In inflammation, however, the role of sodium channels is less well established. Indeed, the lack of a clinical analgesic response to typical systemic sodium channel blockade in states of inflammation w11x suggests that sodium channels play a minimal role in inflammatory allodynia. Our recent studies w10x, however, have shown that a CFA-induced state of inflammation dramatically enhances sodium channel production and that the changes in sodium channel production are rapid and prolonged. The present study
Fig. 1. Changes in paw withdrawal latencies within 24 h of CFA injection. Reductions in the withdrawal latency are seen immediately after CFA injection. Latencies recover to baseline levels within 3 h of injection then progressively decline to maximum effect by 12 h post-injection. Saline-injected and contralateral-control paw withdrawal latencies show a steady decline with repetitive stimulation but do not achieve levels of sensitivity seen in the injected paw.
298
H.J. Gould III et al.r Brain Research 824 (1999) 296–299
Fig. 2. Development of sodium channel labeling in dorsal root ganglia following CFA injection. A contralateral, uninjected-control ganglion as seen with the confocal microscope is depicted in panel ŽA.. The photomicrograph depicts background labeling that is identical to that seen in ganglia associated with hindpaws injected with normal saline at anytime post-injection or with CFA at anytime prior to 23 h post-injection. Sodium channel labeling seen in DRGs ipsilateral to a CFA-injected hindpaw at 23 and 24 h post-injection are depicted in ŽB. and ŽC., respectively. The punctate labeling is thought to reflect increased levels of sodium channel protein in within vesicles of the trans-Golgi network. The ganglion depicted in D was pre-blocked with purified sodium channel following CFA injection into the ipsilateral hindpaw 24 h before perfusion. Calibration bar s 20 mm.
extends these observations and shows that sodium channel augmentation in neurons of all sizes within DRGs begins at 23 h post-injection, approximately 12 h after the development of a prolonged state of allodynia. Furthermore, the number of neurons that demonstrate sodium channel augmentation appears to be proportional to the size of the inducing inflammatory lesion. Although there is a temporal relationship between the development of thermal allodynia
and the augmentation of sodium channel production, a causal relationship between these events is not clear. It is notable, however, that the enhanced sodium channel production is transient in large DRG cells most typically related to populations of large myelinated, Ab and Ad, axons, but only persists in this neuronal population for approximately 2 weeks during the period of thermal allodynia w10x. These results suggest that sodium channel
H.J. Gould III et al.r Brain Research 824 (1999) 296–299
augmentation in the large myelinated neurons may be responsible for the maintenance of the acute phase of inflammatory allodynia perhaps through enhancement of repetitive neuronal activity and the facilitation of the mechanisms of central sensitization. In contrast, augmented sodium channel production persists beyond the period of thermal allodynia in small DRG neurons thought to be related to the unmyelinated, nociceptive C-fibers. It is possible that the persistence of sodium channels in the population of small neurons, rather than maintaining an allodynic state, provides the substrate for the maintenance of spontaneous neuronal activity in DRGs and thus the basis for wound vigilance. The increased sodium channel density in the small neurons alternatively may be more specifically associated with the states of mechanical w16,17x or chemical w12x allodynia that we have not examined.
w7x
w8x
w9x
w10x
w11x
w12x
Acknowledgements HJG and JDE are supported by US Army Medical Research Grant ŽDAMD17-93-V-3013., DP is supported by NIDA Grant ŽDA07379., and SRL is supported by NIH Grant ŽNS34375..
w13x
w14x
w15x
References w1x C. Astrup, Pavlovian Psychiatry—A New Synthesis, Charles C. Thomas, Springfield, IL, 1965. w2x J.N. Campbell, S.N. Raja, R.A. Meyer, S.E. MacKinnon, Myelinated afferents signal the hyperalgesia associated with nerve injury, Pain 32 Ž1988. 89–94. w3x T.R. Cummins, S.G. Waxman, Down-regulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury, J. Neurosci. 17 Ž1997. 3503–3514. w4x M. Devor, The pathophysiology of damaged peripheral nerves, in: P.D. Wall, R. Melzack ŽEds.., Textbook of Pain, Vol. 3, Livingstone, Edinburgh, 1994, pp. 79–100. w5x M. Devor, P. Lomazov, O. Matzner, Sodium channel accumulation in injured axons as a substrate for neuropathic pain, in: J. Boivie, P. Hansson, U. Lindblom ŽEds.., Touch, Temperature, and Pain in Health and Disease: Mechanisms and Assessments, Progress in Pain Research and Management, Vol. 3, IASP Press, Seattle, 1994, pp. 207–230. w6x S.D. Dib-Hajj, J.A. Black, T.R. Cummins, A.M. Kenney, J.D.
w16x
w17x
w18x
w19x
w20x
299
Kocsis, S.G. Waxman, Rescue of a-SNS sodium channel expression in small dorsal root ganglion neurons after axotomy by nerve growth factor in vivo, J. Neurophysiol. 79 Ž1998. 2668–2676. S. Dib-Hajj, J.A. Black, P. Felts, S.G. Waxman, Down-regulation of transcripts for Na channel a-SNS in spinal sensory neurons following axotomy, Proc. Natl. Acad. Sci. USA 93 Ž1996. 14950–14954. S.D. Dib-Hajj, L. Tyrrell, J.A. Black, S.G. Waxman, NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy, Proc. Natl. Acad. Sci. USA 95 Ž1998. . J.D. England, F. Gamboni, M.A. Ferguson, S.R. Levinson, Sodium channels accumulate at the tips of injured axons, Muscle and Nerve 17 Ž1994. 593–598. H.J. Gould III, J.D. England, Z.P. Liu, S.R. Levinson, Rapid sodium channel augmentation in response to inflammation induced by complete Freund’s adjuvant, Brain Res. 802 Ž1998. 69–74. H.J. Gould III, T.N. Gould, S.C. Reeb, D. Paul, The effect of gabapentin on inflammatory pain in rats, Analgesia 3 Ž1997. 131– 139. H.O. Handwerker, Pain producing substances, in: H.W. Kosterlitz, L.Y. Terenius ŽEds.., Pain and Society, Verlag Chemi, Weinheim, 1980, pp. 325–338. K. Hargreaves, R. Dubner, R. Brown, C. Flores, J. Joris, A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia, Pain 32 Ž1988. 77–88. S.D. Novakovic, E. Tzoumaka, J.G. McGivern, M. Haraguchi, L. Sangameswaran, K.R. Gogas, R.M. Eglen, J.C. Hunter, Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions, J. Neurosci. 18 Ž1998. 2174–2187. M.A. Rizzo, J.D. Kocsis, S.G. Waxman, Mechanisms of paraesthesiae, dysaesthesiae, and hyperaesthesiae: role of Naq channel heterogeneity, Eur. Neurol. 36 Ž1996. 3–12. A. Rueff, A.J.L.R. Dawson, L.M. Mendell, Characteristics of nerve growth factor induced hyperalgesia in adult rats: dependence on enhanced bradykinin-1 receptor activity but not neurokinin-1 receptor activation, Pain 66 Ž1996. 359–372. B. Safieh-Garabedian, S. Poole, A. Allchorne, J. Winter, C.J. Woolf, Contribution of interleukin-1b to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia, Br. J. Pharmacol. 115 Ž1995. 1265–1275. M. Tanaka, T.R. Cummins, K. Ishikawa, S.D. Dib-Hajj, J.A. Black, S.G. Waxman, SNS Naq channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model, NeuroReport 9 Ž1998. 967–972. R.F. Thompson, W.A. Spencer, Habituation: a model phenomenon for the study of neuronal substrates of behavior, Psychol. Rev. 73 Ž1966. 16–43. S.G. Waxman, J.D. Kocsis, J.A. Black, Type III sodium channel mRNA is expressed in embryonic, but not adult spinal sensory neurons and is reexpressed following axotomy, J. Neurophysiol. 72 Ž1994. 466–470.