Regulation of cutaneous C-fiber heat nociceptors by nerve growth factor in the developing rat

1. Previous work has indicated that nerve growth factor (NGF) is an important factor for the development of nociceptive A-delta fibers. Here we asked if the availability of NGF during the first 2 wk of development can influence the phenotypic development of unmyelinated afferent C-fibers. 2. To do this, we treated newborn rats with antibodies to NGF from postnatal day (PND) 2-14, a treatment known not to lead to cell death, or with exogenous NGF (PND 0-14). Untreated litter mates served as controls. When the animals were mature (5-20 wk later), they were anesthetized (urethan, 1.25 g/kg ip) and single-unit recordings were made from sural nerve C-fibers in dorsal root filaments. To obtain an unbiased estimate of the physiological types present, an electrocutaneous search technique was employed to isolate the location of the putative receptive field of the C-fiber being studied within the sural nerve territory. This technique enabled us to acquire a sample of C-fibers that was unbiased by natural search stimuli which are often damaging to skin. 3. We found that the proportion of C-fibers that could be driven by noxious heat and mechanical stimuli (C-mechanoheat fibers, C-MH) was reduced from 28% (11/40 fibers) of the sample in controls to 10% (3/31 fibers) in anti-NGF treated animals. The C-MH fibers appeared to have been replaced by a novel type of pressure receptor with an unusually low mechanical threshold (mean 0.86 +/- 0.58 compared with 13.0 +/- 8.3 g for control mechanonociceptors).(ABSTRACT TRUNCATED AT 250 WORDS)

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Leukotriene B4 decreases the mechanical and thermal thresholds of C-fiber nociceptors in the hairy skin of the rat

Journal of Neurophysiology ◽

10.1152/jn.1988.60.2.438 ◽

1988 ◽

Vol 60 (2) ◽

pp. 438-445 ◽

Cited By ~ 61

Author(s):

H. A. Martin ◽

A. I. Basbaum ◽

E. J. Goetzl ◽

J. D. Levine

Keyword(s):

Acetic Acid ◽

Glacial Acetic Acid ◽

Leukotriene B4 ◽

Thermal Stimulation ◽

Mechanical Stimuli ◽

Noxious Heat ◽

C Fibers ◽

Mechanical Threshold ◽

C Fiber ◽

Heat Threshold

1. We have recently shown that leukotriene B4 (LTB4), a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, sensitizes nociceptors to mechanical stimuli. The present study examined whether LTB4 also induces a heat sensitization of cutaneous C-fiber nociceptors. The C-fiber nociceptors studied had von Frey hair thresholds greater than 5 g and were characterized according to their responses to noxious heat and chemical stimuli, including glacial acetic acid, bradykinin, and capsaicin. Thirty-four of the C-fibers that were activated by intense thermal stimulation were also activated by topical application of glacial acetic acid. They were classified as C-polymodal nociceptors (2, 28). Those that were activated by intense mechanical and thermal stimulation, but were unresponsive to acid, were classified as C-mechanoheat nociceptors (27). 2. Ninety-four percent of C-polymodal nociceptors and 60% of C-mechanoheat nociceptors were sensitized by LTB4. All C-fiber nociceptors that showed a decrease of their heat threshold also had a decrease of their mechanical threshold. LTB4 (75 ng) lowered the average heat threshold from 45 degrees C to 35 degrees C and produced an average decrease in the mechanical threshold of 86%. 3. The magnitude of the LTB4-evoked decrease in thermal threshold was similar to that produced by 75 ng of prostaglandin E2 (PGE2). These data demonstrate that LTB4 sensitizes C-mechanoheat nociceptors to both mechanical and thermal stimuli. 4. We conclude that LTB4 may contribute to the component of hyperalgesia that is resistant to nonsteroidal anti-inflammatory agents.

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Rare human nerve growth factor-β mutation reveals relationship between C-afferent density and acute pain evaluation

Journal of Neurophysiology ◽

10.1152/jn.00667.2015 ◽

2016 ◽

Vol 116 (2) ◽

pp. 425-430 ◽

Cited By ~ 7

Author(s):

Irene Perini ◽

Mitra Tavakoli ◽

Andrew Marshall ◽

Jan Minde ◽

India Morrison

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Fiber Density ◽

Nerve Growth ◽

Perceptual Evaluation ◽

Pain Evaluation ◽

C Fibers ◽

Small Fiber ◽

Corneal Confocal Microscopy ◽

C Fiber

The rare nerve growth factor-β (NGFB) mutation R221W causes a selective loss of thinly myelinated fibers and especially unmyelinated C-fibers. Carriers of this mutation show altered pain sensation. A subset presents with arthropathic symptoms, with the homozygous most severely affected. The aim of the present study was to investigate the relationship between peripheral afferent loss and pain evaluation by performing a quantification of small-fiber density in the cornea of the carriers, relating density to pain evaluation measures. In vivo corneal confocal microscopy (CCM) was used to quantify C-fiber loss in the cornea of 19 R221W mutation carriers (3 homozygous) and 19 age-matched healthy control subjects. Pain evaluation data via the Situational Pain Questionnaire (SPQ) and the severity of neuropathy based on the Neuropathy Disability Score (NDS) were assessed. Homozygotes, heterozygotes, and control groups differed significantly in corneal C-nerve fiber density, with the homozygotes showing a significant afferent reduction. Importantly, peripheral C-fiber loss correlated negatively with pain evaluation, as revealed by SPQ scores. This study is the first to investigate the contribution of small-fiber density to the perceptual evaluation of pain. It demonstrates that the lower the peripheral small-fiber density, the lower the degree of reported pain intensity, indicating a functional relationship between small-fiber density and higher level pain experience.

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The 15-lipoxygenase product, 8R,15S-diHETE, stereospecifically sensitizes C-fiber mechanoheat nociceptors in hairy skin of rat

Journal of Neurophysiology ◽

10.1152/jn.1990.63.5.966 ◽

1990 ◽

Vol 63 (5) ◽

pp. 966-970 ◽

Cited By ~ 33

Author(s):

D. M. White ◽

A. I. Basbaum ◽

E. J. Goetzl ◽

J. D. Levine

Keyword(s):

Arachidonic Acid ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Thermal Stimulus ◽

Mechanical Stimuli ◽

Noxious Heat ◽

Lipoxygenase Product ◽

Hairy Skin ◽

Mechanical Threshold ◽

C Fiber

1. This study examined the effects of the 15-lipoxygenase product of arachidonic acid metabolism, (8R,15S)-dihydroxyicosa-(5E-9,11,13Z)tetraenoic acid (8R,15S-diHETE), on mechanical thresholds and thermal responses of saphenous nerve cutaneous C-fiber nociceptors that innervate the hairy skin of the rat hindpaw. Single C-fiber mechanoheat nociceptors (C-MH) that had von Frey hair (VFH) thresholds greater than 5 g and were activated by a noxious heat stimulus were chosen for study. We also studied the effects of prostaglandin E2 (PGE2), a cyclooxygenase product of arachidonic acid metabolism, on these nociceptors. 2. The 63 C-MHs studied had a conduction velocity of 0.82 +/- 0.03 m/s (mean +/- SE) and a mechanical threshold of 13.4 +/- 2.4 g. In a subgroup of these (n = 24), the thermal threshold was measured as (44 +/- 1 degree C) (mean +/- SE). 3. 8R,15S-diHETE produced a significant decrease in mechanical threshold of C-MHs (n = 33). The 8R,15S-diHETE-induced sensitization of C-MHs to mechanical stimuli was completely antagonized by coadministration with a stereoisomer, 8S,15S-diHETE (n = 10). 4. The mechanical threshold of C-MHs (n = 10), previously injected with the combination of 8R,15S-diHETE and 8S,15S-diHETE, was significantly reduced by a subsequent injection of PGE2. In a separate group of C-MHs (n = 7), PGE2 was co-injected with 8S,15S-diHETE, which failed to antagonize the sensitizing effect of PGE2 on mechanical threshold. 5. 8R,15S-diHETE also sensitized C-MHs (n = 9) to a thermal stimulus consisting of 37 degrees C for 5 min.(ABSTRACT TRUNCATED AT 250 WORDS)

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