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PubMed2001

Neurotrophin receptor expression in retrogradely labeled trigeminal nociceptors--comparisons with spinal nociceptors.

In situ hybridization for trkA mRNA in trigeminal ganglion neurons retrogradely labeled with FluoroGold from the mandibular incisor demonstrated limited expression of the high-affinity nerve growth factor (NGF) receptor in this presumptive nociceptor population. Immunocytochemistry using polyclonal anti-trkA antibodies confirmed this result and extended it to show low levels of trkA protein expression in afferents labeled from the cornea. Less than 10% of the cells innervating the incisor, and approximately 15% of those innervating the cornea, were trkA-positive in adult and neonatal mice. This proportion is considerably lower than that observed in Dorsal Root Ganglion nociceptors, in which approximately 80% in neonates and approximately 40% in adults express trkA (Molliver and Snider, J. Comp Neurol 381: 428-438, 1997). Presumptive trigeminal nociceptors were further identified on the basis of expression of Calcitonin gene related peptide. In the entire ganglion, approximately 43% of the trkA-positive cells were CGRP-positive, and approximately 44% of the CGRP-positive cells were trkA-positive. Most trkA-positive cells that were CGRP-negative were medium-to-large diameter, while most of those that were CGRP-positive but trkA-negative were small diameter. Only approximately 5% of trkA-positive cells labeled from the incisor, and approximately 10% from the cornea, were CGRP-positive. Approximately 15% of the corneal or pulpal afferent neurons expressed ret-immunoreactivity. These results suggest that trigeminal nociceptors differ from spinal nociceptors in several significant ways. Differences in neurotrophic requirements may be related to differences in target tissues, in embryonic origin of some trigeminal ganglion cells, or in the timing of down-regulation of trkA expression in trigeminal ganglion cells.

Animals↗
PubMed1982

[Effect of electroacupuncture on the integration of nociceptor and non-nociceptor afferent pathways in the second somatosensory cortex of the cerebral hemisphere].

It was shown in acute experiments on cats tha auricular electroacupuncture (EA) at a frequency of 3 Hz for 15-30 minutes produces an inhibition of evoked potentials (EP) in response to nociceptive stimulation of the dental pulp in the second somatosensory zone of the large hemispherical cortex (C2) up to 40% of the control level. The effect lasts 50-60 minutes. The inhibitory effect is abolished by intravenous injection of naloxone (5 mg/kg). Along with inhibition of nociceptive EP, EA facilitates EP by 75% upon non-nociceptive stimulation of the lower lip for 15-20 minutes. Direct stimulation of C2 produces an inhibition of nociceptive EP in the parafascicular complex of the thalamus. It is suggested that EA stimulates the neuronal populations of C2, which enhances the modulating effects of this zone of the cortex on the transmission of nociceptive information at various levels of the CNS.

Acupuncture Therapy↗
PubMed1996

Mechanical response properties of nociceptors innervating feline hairy skin.

1. The responses of feline cutaneous nociceptors were examined in vivo by systematically manipulating the intensive and spatial dimensions of mechanical stimulation. A computer-controlled motor was used to apply prescribed forces (5-90 g) to a nociceptor's receptive field, with flat-tipped, cylindrical probes of various sizes (contact areas: 0.1-5.0 mm2). The stimulating device and protocols were similar to those previously used to evaluate human perception, thus allowing for comparisons of the two data sets. 2. With a ramp-and-hold stimulus of controlled force, most nociceptors showed a slowly adapting (SA) response throughout the stimulus. In this way, nociceptors resembled low-threshold SA mechanoreceptors. However, in contrast to SA mechanoreceptors, nociceptors failed to exhibit an onset burst of activity associated with the stimulus ramp. Nineteen percent (6 of 31) of the nociceptors often showed the opposite trend during the stimulus, e.g., a gradually increasing firing rate. Most of these nociceptors (5 of 6) had particularly high mechanical thresholds. 3. With 30 stimuli repeated at short intervals (6-8 s), response rates tended to decrease across trials. This phenomenon was most evident with more intense stimuli. When two series of stimuli were separated by 4-5 min, there was no apparent trend of reduced responsiveness between series. 4. Overall, nociceptors responded in an orderly way to variations in force and probe size. For a given probe size, larger forces produced greater responses; for a given force, smaller probes produced greater responses. The relationship between probe size and force was best described as an even tradeoff between force and a linear dimension of the probe (i.e., probe perimeter), rather than the area of the probe. Thus a given pressure (force/area) did not evoke the same response from nociceptors as probe size was varied. 5. There were two significant differences in the mechanical responsiveness between A fiber and C fiber nociceptors. First, for a given set of stimuli, A fiber nociceptors exhibited a greater response rate than the C fiber nociceptors. Second, the A fiber nociceptors exhibited a greater differential response related to probe size than the C fiber nociceptors. On the basis of these two features, the A fiber nociceptors' response profiles showed a closer parallel with previously reported human pain thresholds than the C fiber nociceptors did. 6. When the nociceptors were subdivided as to their mechanical threshold, those with lower thresholds [mechanically sensitive afferents (MSAs)] showed a response saturation with the more intense stimuli. On average, the stimulus levels at which saturation occurred were close to human pain threshold. Those nociceptors with higher thresholds [mechanically insensitive afferents (MIAs)] did not show such saturation. Thus only the MIAs appeared to have the capacity to unambiguously encode mechanical stimulus intensities above pain threshold. The MSAs, on the other hand, exhibited their greatest dynamic response range near the threshold for nonpainful sharpness. Thus the group of afferents commonly defined as nociceptors exhibit a heterogeneity of mechanical response properties, which may serve functionally different roles for perception.

Action Potentials↗
PubMed1997

[What is a nociceptor?].

INTRODUCTION: Nociceptors can be defined as sensory receptors that are activated by noxious stimuli that damage or threaten the body's integrity. Nociceptors belong to the slowly conducting afferent A delta and C fibres. They are classified according to their responses to mechanical, thermal, and chemical stimuli. SKIN NOCICEPTORS: In the skin, high-threshold mechano-nociceptors (HTMs) and mechano-heat nociceptors of A and C fibres (AMHs and CMHs) are frequently found. CMHs are usually called polymodal C fibres (CPMs) if they also show chemosensitive properties. Sensations of sharp pain are evoked by intraneural microstimulation of nociceptive A delta fibres, whereas stimulation of C fibres causes dull pain sensations. NOCICEPTORS OF DEEP TISSUES AND VISCERA: Slowly conducting afferents of deep tissues (muscles, joints) are primarily classified according to their mechanosensitivity. High-threshold afferents in somatic and visceral tissues are specifically activated by noxious mechanical stimuli. Many visceral afferents, however, are already activated by peristaltic contractions encoding the stimulus intensity over a wide range. High proportions of somatic and visceral nociceptors can be excited or sensitised by various irritants and inflammatory mediators such as capsaicin, bradykinin, prostaglandins, leukotrienes, serotonin, histamine, and free radicals. As a special class of nociceptors, mechano-insensitive or "silent" afferents have been found in nearly all tissues. Silent afferents become mechanosensitive only after long noxious stimulation, e.g., during an inflammation. FREE NERVE ENDINGS: "Free nerve endings", which are regarded as the morphological correlatives of nociceptors, usually consist of bundles of unmyelinated fibres. With electron microscopy varicose segments of the sensory axon are visible that are characterised by free areas of axolemma, accumulations of mitochondria and vesicles, and a modified axoplasm. These presumptive receptive sites are periodically arranged along the whole course of the sensory endings at a length of up to several hundred microns. Additionally, the fine sensory endings are branched, forming tree-like structures, and frequently innervate different types of tissues. Studies correlating structure and function of articular afferents provide evidence for a close relationship between topographical and functional properties of sensory endings. High-threshold afferents (nociceptors) seem to terminate in structures of dense connective tissue. Proportions of nociceptors contain neuropeptides such as substance P and calcitonin gene-related peptide, which are released from the activated nociceptive terminals and cause neurogenic inflammation, including precapillary vasodilatation and postcapillary plasma extravasation. PAIN TREATMENT: Experimental and clinical progress has been achieved in using the nociceptor as a target for chemical anti-nociception and treatment of pain. Substances that act directly or indirectly on the nociceptor are steroidal and non-steroidal analgesics, capsaicin analogs, bradykinin antagonists, opioids, and (in the trigeminal system) 5-hydroxytryptamine agonists.

Animals↗
PubMed1997

Responses of cutaneous A-fiber nociceptors to noxious cold.

Responses of cutaneous nociceptors to natural stimuli, particularly mechanical and heat stimuli, have been well documented. Although nociceptors are excited by noxious cold stimuli, there have been few studies of their stimulus-response functions for cold stimuli over a wide range of stimulus temperatures. Furthermore, the proportion of nociceptors excited by noxious cold is not clear. In the present study, we examined responses of mechanosensitive A delta-nociceptors and low-threshold mechanoreceptors to a wide range of cold stimuli that included stimulus temperatures <0 degrees C. Electrophysiological recordings were made from single primary afferent fibers in the saphenous nerves of anesthetized rats. Cutaneous sensory receptors were classed according to their conduction velocity and subgrouped functionally according to their responses evoked by mechanical, heat, and cold stimuli (0 degrees C). Responses evoked by a wide range of cold stimulus intensities that included stimuli considered innocuous and noxious (painful) were then assessed. Stimuli of 20 to -20 degrees C were delivered to the receptive field via a 1-cm2 contact thermode from a base temperature of 32 degrees C. Stimuli were applied in descending order of 2 degrees C decrements. Stimulus ramp rate was 5 degrees C/s, and stimulus temperatures were applied for a duration of 10 s. A total of 90 A fibers was studied, of which 61 were nociceptors and had conduction velocity in the A delta-range (2-30 m/s). Nociceptors were classed initially as mechanical, mechanoheat, and mechanocold nociceptors. The remaining 29 fibers were low-threshold mechanoreceptors with conduction velocity in the A delta- or A beta-range (>30 m/s). These were subgrouped according to their adaptive properties as slowly or rapidly adapting, and according to whether they were excited by hair movement (hair follicle afferent fibers). All nociceptors were excited by noxious cold. Only 30% of nociceptors were considered sensitive to cold on initial classification with the use of a cold stimulus of 0 degrees C. However, all nociceptors were excited by stimulus intensities <0 degreesC. Response thresholds for cold ranged from 14 to -18 degrees C (-4.6 +/- 1.07 degrees C, mean +/- SE). The total number of impulses, discharge rate, and peak discharge increased monotonically as intensity of cold stimuli increased. Power functions were used to determine the rate at which the number of impulses increased as stimulus intensity increased. The slopes of power funcions ranged from 0.12 to 2.28 (mean 1.07 +/- 0.13). Most mechanoreceptors were not excited by cold stimuli. The only types of mechanoreceptors that responded reliably to cold stimuli were the slowly adapting mechanoreceptors. Responses usually occurred during the temperature ramp when the skin temperature was decreasing. There was no evidence that mechanoreceptors encoded the intensity of cold stimuli at intensities above or below 0 degrees C, because evoked responses did not increase with intensity of cold stimuli. It is concluded that the proportion of cutaneous A delta-nociceptors excited by noxious cold stimuli has been underestimated in previous studies. All nociceptors were excited by stimulus temperatures <0 degrees C and encoded the intensity of cold stimuli. It is therefore likely that cutaneous A delta-nociceptors contribute to the sensation of cold pain, particularly pain produced by stimulus temperatures <0 degrees C.

Action Potentials↗
PubMed2004

Characteristics of nociceptors in the periodontium--an in vitro study in rats.

Recent studies have indicated that nociceptors can be classified into various types according to their physiological properties. These studies have clarified that the frequency distribution of various nociceptor types is different among body sites and animal species. In the present study, we investigated the physiological properties of rat's periodontal nociceptors in an in vitro jaw-nerve preparation. Responses were recorded from functional single filaments in the inferior alveolar nerve. To determine the nociceptor type, calibrated von Frey filaments, heat, and bradykinin (BK) stimuli were used. We found five subtypes of nociceptors in the periodontal ligaments of the lower incisor: Adelta-high threshold mechanonociceptors (Adelta-HTM, n=28), Adelta-mechanoheat nociceptors (Adelta-MH, n=6), Adelta-polymodal nociceptors (Adelta-POLY, n=26), C-high threshold mechanonociceptors (C-HTM, n=3) and C-polymodal nociceptors (C-POLY, n=4). Most nociceptors were Adelta-innervated, while only a small number of C-innervated nociceptors were found. The present results suggest that periodontal nociceptors transmit mainly fast pain, and may thus play a role in rapid detection of injure-related stimuli during mastication.

Animals↗
PubMed1999

Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat.

Tissue injuries commonly cause an increase in pain sensitivity, so that normally painful stimuli become more painful (hyperalgesia), and those usually associated with nonnoxious sensations evoke pain (allodynia). The neural bases for these sensory phenomena have been explored most extensively using heat injuries and experimental arthritis as models. Heat sensitization of cutaneous nociceptors is observed after burns, and sensitization of articular afferents to limb movements occurs after knee joint inflammation. These are likely to be peripheral mechanisms of hyperalgesia. Others, using different models of peripheral inflammation, have only rarely found mechanical sensitization of cutaneous nociceptors. In general these studies have failed to evaluate suprathreshold mechanical sensitivity, which has led to the concept of enhanced spinal cord processing ("central sensitization") serving as the neural substrate for mechanical hyperalgesia. In the current experiments, the mechanical and heat responses of cutaneous nociceptors supplying the glabrous skin of the rat hindpaw were studied 16-24 h after induction of acute inflammation with complete Freund's adjuvant. Single-fiber recordings were made from nociceptors in the sciatic nerve of barbiturate-anesthetized animals, and their responses compared with those obtained from nociceptors tested identically in normal animals. Nociceptors were characterized by the following: 1) graded mechanical stimuli (5-90 g) delivered with probes of tip area of 1 and 0.1 mm(2), 2) their adaptive responses to 2-min mechanical stimuli at three intensities, and 3) their responses to graded heat stimuli (40-50 degrees C). Forty-three nociceptors were studied in the inflamed state; 20 were A fibers, and the remainder were C fibers. Mechanical thresholds, determined with calibrated monofilaments, were not significantly different from controls. Sensitization to suprathreshold mechanical stimuli was observed for both A- and C-fiber nociceptors, although it was greater for the A fibers. Similarly, sensitization during testing of adaptive properties of A- and C-fiber nociceptors was seen, although it was limited to the dynamic (initial) and not the static (plateau) phase of the response. Heat sensitization was observed in 25% of A-fiber nociceptors, but the responses of C fibers to heat were depressed. Other indicators of neuronal sensitization, such as spontaneous activity and expanded receptive fields, were also observed. It was concluded that the mechanical hyperalgesia caused by peripheral inflammation could be explained by nociceptor sensitization. Central mechanisms cannot be completely ruled out as contributing to such hyperalgesia, although their role may be much smaller than previously envisaged.

Analysis of Variance↗
PubMed1999

Recent advances in neuropharmacology of cutaneous nociceptors.

Cutaneous nociceptors are peripheral receptive endings of primary sensory neurons activated by noxious stimuli. Nociceptors detect and signal the presence of tissue-damaging stimuli or the existence of tissue damage. In this short review, we will focus on the molecular mechanism of maintenance, activation, inhibition and sensitization in cutaneous nociceptors. Neurotrophic factors are essential to the development of nociceptors during embryogenesis. Recent evidences have indicated that nociceptors in the adult are maintained by either nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF). A selective activator of nociceptors is capsaicin, natural product of capsicum peppers. Recently, the receptor for capsaicin (the vanilloid receptor 1: VR1) has been cloned, identified and characterized. VR1 seems to play an important role in the activation and sensitization of nociceptors. In contrast, peripheral endogenous cannabinoids such as anandamide are novel candidates for mediators that inhibit the excitation of nociceptors. Intracellular messengers and the mechanisms of signal transduction in nociceptors have also been studied. Our recent findings provide evidences demonstrate that an activation of both cAMP- and cGMP-second messenger systems is required to induce the sensitization of nociceptors. Such emerging evidences reviewed here would make a significant contribution to further understanding of the molecular mechanism of nociceptors.

Animals↗
PubMed2005

Postherpetic neuralgia: topical lidocaine is effective in nociceptor-deprived skin.

OBJECTIVES: Topical lidocaine is effective in postherpetic neuralgia (PHN). The aim of the present investigation was to classify patients according to their predominant peripheral nociceptor function and to compare these data with the results of a controlled study using dermal lidocaine patch. METHODS: Within the skin area of maximal pain QST (thermotest) and QCART (histamine iontophoresis and laser Doppler flowmetry) were performed prospectively in 18 PHN patients. A controlled study using cutaneous lidocaine (lidocaine 5% patch, IBSA) followed. RESULTS: Six patients (group I, sensitised nociceptors) had no sensory loss. Heat pain thresholds were equal or lower than on the contralateral side. Histamine-induced flare and axon reflex vasodilatation were not different on both sides. Histamine evoked pain increased. In 12 patients (group II, nociceptor impairment) heat pain thresholds were higher than contralateral. Histamine-induced flare was impaired or abolished. Histamine did not induce any sensation. Lidocaine was efficacious in the entire group of patients. Subgroup analysis revealed that patients with impairment of nociceptor function had significantly greater pain reduction under lidocaine vs placebo. Patients with preserved and sensitised nociceptors demonstrated no significant pain relief. CONCLUSIONS: PHN patients differ concerning their cutaneous nociceptor function: In the group I pain is caused by pathologically sensitised nociceptors. In subset II there is a loss of function of cutaneous C-nociceptors within the allodynic skin. Patients responded well to topical lidocaine even if the skin was completely deprived of nociceptors. Different underlying mechanisms of lidocaine action in nociceptor-deprived skin are discussed.

Administration, Cutaneous↗
PubMed1997

Characteristics of mucosal nociceptors in the rat oral cavity: an in vitro study.

Characteristics of mucosal nociceptors were investigated by recording activities from single fibers in the lingual nerve in an in vitro jaw-nerve preparation of rats. We found four subtypes of nociceptors in the medial side gingival area of the oral mucosa in the lower jaw: 11 A delta-high threshold mechanonociceptors (A delta-HTMs), 7 A delta-mechanoheat nociceptors (A delta-MHs), 21 A delta-polymodal nociceptors (A delta-POLYs) and 28 C-polymodal nociceptors (C-POLYs). Thus the majority of the nociceptors was polymodal type (ca. 73% of the recorded fibers), ca. 43% of which consisted of A delta-POLYs scarcely found in the skin but commonly found in the deep tissue, muscle or colon. In contrast to the skin, the size of the receptive field of both A delta and C polymodal types was larger than that of either A delta-HTM or A delta-MH type. The von Frey threshold of all types of mucosal nociceptor was higher than that of the skin, though their heat threshold was almost the same as that of the skin nociceptors. These results show that the mucosal nociceptors are different from the skin nociceptors in the frequency distribution of their types and certain physiological properties.

Action Potentials↗
PubMed1996

Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: behavioral evidence.

Several lines of evidence suggest that different classes of nociceptive afferents mediate the responses produced by different rates of noxious skin heating. More specifically, low skin heating rates evoke nociceptive responses that appear to be mediated by the activation of capsaicin-sensitive C-fiber nociceptors, whereas high skin heating rates appear to produce responses mediated by the activation of other nociceptors. This hypothesis was examined by both electrophysiological and behavioral experiments. This report describes the results of experiments designed to determine whether pharmacologic treatments that selectively alter the activity of C-fiber nociceptive afferents also produce selective effects on foot withdrawal responses to either high or low rates of noxious foot heating. The results of these experiments demonstrate that: (1) topical application of a low concentration of capsaicin, which sensitizes C-fiber nociceptors, selectively decreased the latency of responses to low heating rates; (2) topical application of a high concentration of capsaicin, that desensitizes C-fiber nociceptors, selectively increased the latency of responses to low heating rates; (3) low doses of systemic morphine, which selectively attenuate nociception produced by the activation of C-fiber nociceptors, selectively increased response latencies for low skin heating rates. These results support the conclusion that foot withdrawal responses evoked by low skin heating rates are mediated by the activation of capsaicin-sensitive C-fiber nociceptors and foot withdrawal responses evoked by high skin heating rates are mediated by the activation of other nociceptors. This conclusion is supported by the results of the accompanying electrophysiological study which provides direct evidence that low rates of skin heating preferentially activate C-fiber nociceptors while high rates of skin heating preferentially activate A delta nociceptors.

Administration, Cutaneous↗
PubMed2001

Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin.

1. ATP can elicit pain in humans and, together with other P2X channel agonists, can produce nocifensive responses in rodents. We used the rat in vitro skin-nerve preparation to quantify primary afferent responses to ATP and its stable analogue alpha,beta-methylene ATP in normal and carrageenan-inflamed skin. 2. Both ATP and alpha,beta-methylene ATP were found to specifically activate the peripheral terminals of Adelta and C-fibre nociceptors in the skin. Thirty-nine per cent of the nociceptors tested responded to the maximal dose of alpha,beta-methylene ATP (5 mM). In contrast, non-nociceptive, low-threshold mechano-sensitive fibres were never activated by the same agonist concentrations. 3. Amongst the nociceptor population, C-mechanoheat fibres (C-MH or polymodal nociceptors) were markedly more responsive to P2X agonists than mechanonociceptors (C-M nociceptors) with Adelta- or C-fibre axons. Both C-mechanoheat and C-mechanonociceptors were activated by alpha,beta-methylene ATP doses as low as 50 microM. 4. In skin inflamed with carrageenan 3-4 h before recording both the number of responsive C-fibre nociceptors and their response magnitude increased. The increased neural response under inflammatory conditions was largely observed in C-mechanoheat or polymodal nociceptors. After low doses of P2X agonists C-MH fibres but not C-M fibres developed elevated ongoing activity and this effect was only seen after carrageenan inflammation. The time course of alpha,beta-methylene ATP-evoked discharges in nociceptors was found to correlate well with the time course of behavioural nocifensive responses in rats to the same agonist described in a previous study (Hamilton et al. 1999). 5. We conclude that the rapid increase in the number of alpha,beta-methylene ATP responsive nociceptors and the increased magnitude of the neural response following carrageenan inflammation explains why very low concentrations of such agonists can cause pain in inflammatory states.

Adenosine Triphosphate↗
PubMed1988

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

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.

Action Potentials↗
PubMed1999

Peripheral coding of tonic mechanical cutaneous pain: comparison of nociceptor activity in rat and human psychophysics.

These experiments investigated temporal summation mechanisms of tonic cutaneous mechanical pain. Human volunteers provided psychophysical estimates of pain intensity, which were compared with discharge patterns of rat cutaneous nociceptors tested with identical stimulus protocols. Human subjects made either intermittent or continuous ratings of pain intensity during stimulation of the skin between the thumb and first finger. Stimulus intensities of 25, 50, and 100 g were applied with a probe of contact area of 0.1 mm(2) for 2 min. Pain perception significantly increased during stimulation (temporal summation) for the 50- and 100-g stimulus intensities. Sequential conduction block of the myelinated fibers supplying the stimulated skin was used to investigate the role of A-fiber mechanoreceptors and nociceptors in this temporal summation. Conduction block of the Abeta fibers resulted in an increase in mechanically evoked pain estimates and an increase in temporal summation, consistent with loss of Abeta-mediated inhibition. When only conduction in the unmyelinated fibers remained, pain estimates were reduced to the preblock levels, but temporal summation was still present. Electrophysiological recordings were made from filaments of the sciatic nerve supplying receptors in the plantar skin of barbiturate-anesthetized rats. Forty units fulfilled the identification criteria for nociceptors: 20 A-fiber and 20 C-fiber nociceptors. Each unit was characterized by recording its responses to graded mechanical and heat stimuli. Nociceptors were also tested with stimuli identical to those applied to the human subjects. The responses of all units to sustained mechanical stimuli were adaptive-that is, they exhibited a gradual decline in response with time. However, the time course of adaptation varied among units. All the C-fiber nociceptors and one-half of the A-fiber nociceptors had rapidly adapting responses. The remainder of the A-fibers displayed slowly adapting responses. One-third of all units also showed short-duration increases in firing rate during stimulation. The latency after stimulus onset of this rate acceleration was inversely related to stimulus intensity. Despite the apparent disparity between perceptual temporal summation and nociceptor adaptation, central and peripheral mechanisms are proposed that can reconcile the relationship between nociceptor activity and pain perception.

Adult↗
PubMed2003

Quantitative single-cell differences in mu-opioid receptor mRNA distinguish myelinated and unmyelinated nociceptors.

A remarkable feature of opioids is that they inhibit pain that persists from previous injuries without eliminating either the initial pain of a new injury or the protective reflexes triggered by it. Here we ask whether selective expression of the mu-opioid receptor (MOR) gene in primary nociceptors (pain-sensing neurons) might contribute to this aspect of opioid specificity. We quantified single-cell levels of MOR mRNA and measured opioid inhibition of Ca channels on identified nociceptors and low-threshold mechanosensors (non-nociceptors) isolated from rats. Negligibly few non-nociceptors express MOR mRNA, thereby rendering nonpain sensations insensitive to opioids. Nearly half of nociceptors of all size classes also fail to express MOR mRNA or to respond to opioids. Among the opioid-responsive nociceptors, a gene dose-response relationship exists such that maximal opioid inhibition occurs when the MOR mRNA concentration of a cell is >15 pm. Almost all large, myelinated nociceptors express MOR mRNA below this level, whereas small, unmyelinated nociceptors are likely to express above it. Because myelinated nociceptors mediate anti-nociceptive reflexes, the data suggest that fine control of the MOR mRNA level contributes to a complex neural trait: the ability of opioids to suppress persistent pain without preventing response to a new injury.

Analgesics, Opioid↗
PubMed2002

Tumour necrosis factor-alpha, interleukin-1beta and interleukin-8 induce persistent mechanical nociceptor hypersensitivity.

It has been previously described that daily intraplantar (i.pl.) injections of prostaglandin E2 (PGE2) and dopamine in rats for 14 days cause the development of a persistent mechanical nociceptor hypersensitivity state lasting more than 30 days. Considering that during inflammation, the release of these hyperalgesic agents are mediated by cytokines, we investigated in the present study whether interleukin-1beta (IL-1beta), IL-8 and tumour necrosis factor-alpha (TNF-alpha) are able to induce persistent mechanical nociceptor hypersensitivity. Daily i.pl. administration of TNF-alpha, IL-1beta or IL-8 for 18 days led to persistent mechanical nociceptor hypersensitivity, which lasted at least 30 days after the cessation of treatment. The co-treatment of the animals with IL-1beta plus indomethacin, but not with atenolol, prevented the induction of persistent mechanical nociceptor hypersensitivity. The co-treatment of the animals with IL-8 plus atenolol, but not with indomethacin, prevented the induction of persistent mechanical nociceptor hypersensitivity. The daily co-treatment of TNF-alpha with either indomethacin or atenolol partially inhibited (+/-50%) the induction of persistent mechanical nociceptor hypersensitivity. However, the combined treatment with indomethacin plus atenolol abolished the induction of the persistent mechanical nociceptive hypersensitivity by TNF-alpha.A single injection of cytokines in the contralateral paws of the animals with persistent hypersensitivity caused only an acute nociceptive response. This observation, together with the demonstration of undetectable levels of immunoglobulins against TNF-alpha, IL-1beta or IL-8 in the sera of animals after the development of the persistent hypersensitivity induced by those cytokines, indicate that this event is not due to an ongoing immunological response against the cytokines. In conclusion, our results support the suggestion that IL-1beta- and IL-8-induced persistent mechanical nociceptor hypersensitivity results from the endogenous release of eicosanoids and sympathetic amines, respectively. However, TNF-alpha-induced mechanical nociceptor hypersensitivity results from the concomitant endogenous release of eicosanoids and sympathomimetic mediators.

Adrenergic beta-Antagonists↗
PubMed1999

The changing sensitivity in the life of the nociceptor.

Plasticity of the central nervous system has been shown to be an important correlate in the generation of chronic pain. However, there is now also increasing evidence for profound changes of the primary sensory neurons including nociceptors throughout the life of an organism and these changes account for clinically relevant alterations of pain perception. During development sensory neurons require one or more growth factors that rescue neurons during critical periods of programmed cell death and growth factors also play an important role for the development of the appropriate phenotype. Neurotrophin-3 may initially have an effect on proliferation of many subtypes of sensory neurons including cells destined to become nociceptors during early development. During a critical period of late prenatal development nerve growth factor (NGF) signalling through its cognate high affinity receptor trkA has been shown to be the main survival factor during a critical period of prenatal development. Humans deficient of trkA suffer from the rare disorder of congenital analgesia. Postnatally, the subpopulation of non-peptidergic nociceptors lose their ability to respond to NGF, start to express receptor element for and begin to respond to glial cell line-derived neurotrophic factor (GDNF). Both NGF and GDNF have also been shown to regulate the sensitivity of nociceptors to heat and capsaicin in the adult. Changes in the levels of endogenous trophic factors have also been implicated for the generation of ongoing activity and sensitisation to heat that are the hallmark of nociceptors innervating inflamed tissue. Whereas the development of ongoing activity correlates with the intensity of ongoing pain, sensitisation of nociceptors to heat can explain the hyperalgesia to heat that typically accompanies inflammatory lesions in the skin. Dramatic changes of nociceptor phenotype occur following nerve injury. Sensory neurons, including nociceptors, start to express adrenoceptors and become responsive for catecholamines and these changes appear to be responsible for the development of sympathetically maintained pain in some patients.

Animals↗