Aδ Nociceptors Research Articles

Is the R3 component of the human blink reflex nociceptive in origin?

The R3 component of the blink reflex can reproducibly be evoked by noxious stimulation but can probably also be elicited by innocuous stimuli. This study was conducted to investigate the contribution of nociceptive Aδ and C fibers to the generation of the electrically evoked R3 blink reflex. Electrical thresholds for detection, pain and all blink reflex components were determined and the modulatory effects of local anesthesia were investigated. The electrical R3 threshold of 4.6±0.5 mA (mean±SE) corresponded to 2.9 times the detection threshold and to 0.35 times the pain threshold. The R3 threshold was significantly below the pain threshold. Under local anesthesia of the supraorbital skin with a complete loss of warm and cold sensation, a loss of pinprick sensation, but a normal detection of tactile stimuli, the electrical pain threshold increased, all other thresholds remained unchanged. Under local anesthesia none of the reflex components were significantly reduced. Cutaneous Aβ fibers and nociceptive Aδ fibers, but not unmyelinated C fibers, contribute to the generation of the electrically evoked R3 component. According to the recruitment order in peripheral sensory nerves the electrical threshold of the R3 is mainly determined by activation of Aβ fibers. Thus, it can not be assumed that the electrically evoked R3 is an adequate model to investigate nociceptive processing.

Topographical distribution of pinprick and warmth thresholds to CO 2 laser stimulation on the human skin

We studied the topographical distribution of laser sensory thresholds on the human hairy skin, using a small laser beam for pinprick and a large beam for warmth sensations. The threshold for pinprick sensation correlated positively with the distance from the brain, suggesting that Aδ nociceptors, the fibers which convey pinprick sensation, are more dense at proximal than at distal body sites. This finding adds information to skin biopsy studies of epidermal free nerve endings which showed a similar gradient, but could not differentiate small myelinated from unmyelinated fiber afferents. Possibly because of a diffuse low density of warmth receptors, laser warmth thresholds showed no trend.

Role of histamine H 1 receptor in pain perception: a study of the receptor gene knockout mice

To study the participation of histamine H 1 receptors in pain perception, histamine H 1 receptor knockout mice were examined for pain threshold by means of three different kinds of nociceptive tasks. These included assays for thermal nociception (hot-plate, tail-flick, paw-withdrawal), mechanical nociception (tail-pressure), and chemical nociception (abdominal constriction, formalin test, capsaicin test) which evoked pain by the activation in nociceptive Aδ and C fibers. The mutant mice lacking histamine H 1 receptors showed significantly fewer nociceptive responses to the hot-plate, tail-flick, tail-pressure, paw-withdrawal, formalin, capsaicin, and abdominal constriction tests. Sensitivity to noxious stimuli in histamine H 1 receptor knockout mice significantly decreased when compared to wild-type mice. This data indicates that histamine plays an important role in both somatic and visceral pain perceptions through histamine H 1 receptors. The difference in the effect of histamine H 1 receptors antagonist, the active ( d-) and inactive ( l-) isomers of chlorpheniramine on ICR mice further substantiates the evidence of the role of histamine H 1 receptors on pain threshold.

Mechanosensory Neurons InnervatingAplysiaSiphon Encode Noxious Stimuli and Display Nociceptive Sensitization

Numerous studies of learning and memory in Aplysia have focused on primary mechanosensory neurons innervating the siphon and having their somata in the left E (LE) cluster of the abdominal ganglion. Although systematic analyses have been made of the responses of these LE cells to mechanical stimulation of the tightly pinned siphon, little is known about corresponding responses when the siphon is unrestrained. The present study demonstrates that LE mechanosensory thresholds in the freely moving siphon are much higher than in the pinned siphon. Light tactile stimuli adequate to activate central neurons and reflexive siphon movements often fail to activate the LE cells when the siphon is unrestrained. Because the LE cells display increasing discharge to increasing pressures, with maximal activation by crushing or tearing stimuli that cause tissue injury, they satisfy accepted definitions of nociceptor. Indeed, they show similarities to vertebrate Adelta nociceptors, including a property apparently unique (among primary afferents) to nociceptors-sensitization by noxious stimulation of their receptive field. Either pinching or pinning the siphon decreases LE cell mechanosensory threshold and enhances soma excitability. Such stimuli reduce effective tissue compliance and cause neuromodulation that enhances sensory responsiveness. These results, and recent descriptions of predatory attacks on Aplysia, suggest that LE sensory neurons are tuned to grasping and crushing stimuli that threaten or produce bodily harm. LE cell sensitization has effects, resembling hyperalgesia and allodynia, that compensate for loss of sensory function during injury and help protect against subsequent threats.

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

Behavioral nociceptive responses evoked by relatively high rates of noxious radiant skin heating appear to be mediated by Aδ nociceptor activation, whereas responses evoked by low rates of skin heating appear to be mediated by the activation of C-fiber nociceptors. This hypothesis was confirmed by the results of single unit recordings of Aδ and C nociceptive afferent fibers isolated from the saphenous nerves of pentobarbital anesthetized rats. Heating the hind paw skin of the rat at a relatively high rate of 6.5°C/sec activated Aδ units within 2 sec after the onset of the stimulus. This response latency is similar to the 2.5 sec latency of the foot withdrawal response to a similar stimulus. In contrast, C-fibers were only slightly activated at a longer latency of 5–6 sec. Conversely, heating the hind paw skin at a relatively low rate of 0.9°C/sec activated C-fibers, but evoked only a few action potentials in Aδ nociceptors. C-fibers began firing at a rate less than 1 Hz between 8 and 10 sec after the onset of heating and fired at a mean rate of 1.5 Hz between 10 and 12 sec, which corresponds to the latency of the foot withdrawal response. Topical application of capsaicin to the hind paw skin decreased the latency of C-fiber responses from control values of 8–12 sec to approximately 4 sec after topical capsaicin treatment. The mean latency of the foot withdrawal response to skin heating at the low rate is also reduced from control values of 12–14 sec to 4–5 sec after capsaicin treatment. In contrast, capsaicin treatment did not significantly affect the responses of Aδ nociceptors. These results support the conclusion that nociceptive foot withdrawal responses to a low rate of skin heating are mediated predominantly by the activation of C-fiber nociceptors. These results provide direct evidence that, under the conditions of these experiments, nociceptive foot withdrawal responses evoked by high rates of skin heating are primarily mediated by Aδ nociceptors, and foot withdrawal responses evoked by low rates of skin heating are primarily mediated by C-fiber nociceptors.

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 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 Aδ nociceptors.

Excitation of rat cutaneous nociceptors by noxious cold

Electrophysiological recordings were made from mechanosensitive nociceptors innervating hairy skin of the rat hindpaw, and responses evoked by a wide range of noxious cold stimuli (20 to −12°C) were determined. All Aδ and C nociceptors sampled were excited by noxious cold. Response thresholds of Aδ nociceptors were significantly higher (colder stimulus temperatures) than thresholds of C fibers, and many exhibited response thresholds below 0°C. Responses of both classes of nociceptors increased as stimulus temperature decreased. These data demonstrate that Aδ and C nociceptors are excited by a wide range of cold stimuli and suggest that the proportion of cutaneous nociceptors excited by noxious cold has been underestimated in previous studies.

Studies of heat pain sensation in man: perception thresholds, rate of stimulus rise and reaction time

Afferent impulse frequency, one of the determinants of subjective magnitude of sensation, varies with the rate of rise of stimulus intensity: the faster the increase in stimulus energy, the higher the frequency of firing for a given amount of energy. This predicts that the steeper the stimulus ramp the lower will be the threshold for perception. While such inverse relation holds for myelinated fibre mediated cold sensation and mechanical pressure sensation, the opposite has been reported for unmyelinated fibre mediated heat pain and cold pain sensations. These paradoxical results intuitively suggest possible reaction time artefact. Indeed, a fixed time interval that includes conduction of the impulses to the brain, central processing and efferent conduction, intervenes between sufficient peripheral stimulus and the voluntary signal in reaction to subjective experience. As stimulus temperature continues to rise along this time, an artefactually high threshold reading results: the steeper the temperature rise, the larger will be the artefact, particularly for submodalities with longer reaction time. The present study compared heat pain threshold, obtained through a method that involves reaction time participation, with heat pain thresholds obtained bypassing reaction time. It was found in 16 volunteers that: (a) Heat pain thresholds decreased as the rate of temperature rise increased when reaction time was not a factor ( P < 0.001). (b) Heat pain thresholds determined through the method involving reaction time participation were significantly higher than those obtained bypassing reaction time ( P <0.01). Such difference increased with increasing rates of temperature rise, (c) Peripheral conduction velocity calculated from average reaction time was found to be approximately 0.6 m/sec. This indicates that at the rates of temperature rise utilized for the present study, heat pain thresholds reflect activity in unmyelinated C nociceptors rather than in small myelinated Aδ nociceptors.

Peripheral projections of nerve fibres in the human median nerve

Elementary sensations of definable quality were evoked by intraneural electrical stimulation of sensory units through tungsten microelectrodes inserted in the median nerve of awake human subjects. The most commonly reported sensations were tapping, pressure, dull pain and sharp pain, which correlated with recording from RA units, SA I units, C nociceptors and Aδ nociceptos, respectively. All sensations were projected more often to the fingertips than to the palm. The multifocal projections of sensations recruited by excitation of small groups of neighbouring nerve fibres were significantly more scattered in space than anticipated if these fibres had preserved an orderly intraneural map, implying lack of somatotopy in the nerve. Mean projected field sizes were 3.4 mm 2 for sharp pain, 9.2 mm 2 for tapping/vibration, 29.3 mm 2 for pressure and 35.4 mm 2 for dull pain, and in addition the latter two showed a rising size gradient from fingertip to palm. Consideration of projected field size as a variable in discriminative touch suggests that input from RA units and Aδ nociceptors may be of importance in stimulus localization, while SA I units may play an additional role in two point discrimination.

Peripheral neural correlates of magnitude of cutaneous pain and hyperalgesia: a comparison of neural events in monkey with sensory judgments in human.

Peripheral neural correlates of magnitude of cutaneous pain and hyperalgesia: a comparison of neural events in monkey with sensory judgments in human.

Latencies of chemically evoked discharges in human cutaneous nociceptors and of the concurrent subjective sensations

Percutaneous recordings from single nociceptive Aδ- and C-fibres have been performed from the superficial radial nerves of conscious human subjects. Nociceptors were tested with a chemical irritant substance, which induced a burning sensation when applied to the intact skin. A comparison of the onset of spike discharges in nociceptors and the onset of the subjective burning sensation indicated that under the conditions of our experiments summation of input from nociceptors is needed in order to induce pain sensations. In particular, our results indicate spatial summation.