Adelta Nociceptors Research Articles

Sensory determinants of thermal pain.

It is still unclear whether the quality of painful thermal sensation is determined only by conduction in specific, dedicated nociceptive channels (i.e. C or Adelta nociceptors) or whether it is a result of integrated activity in both nociceptive and non-nociceptive systems. To evaluate this question, we conducted quantitative and qualitative somatosensory testing in spinal cord injury subjects who suffered from partial or complete loss of thermal sensibility. Testing was performed in skin areas, below the level of the lesion, which were either lacking any thermal sensibility, lacking only one thermal sensation (either heat or cold) or having normal thermal sensations. We found that, in areas lacking any thermal sensibility, warm and cold stimuli produced a sensation of pricking pain, which had no thermal quality and was detected at significantly higher thresholds than in normal controls (48.5 +/- 1.8 and 9.7 +/- 5.1 degrees C for noxious heat- and noxious cold-induced pricking pain, respectively). Normal thermal pain sensations, consisting of normal perception of thermal quality and normal mean pain thresholds, were present both in normal skin areas (42.1 +/- 1.9 and 27.6 +/- 2.25 degrees C for heat and cold pain, respectively) and in areas in which only one thermal modality remained intact, when tested for that modality. Thus, testing for heat pain in areas in which only warm sensation was intact, or cold pain when only cold was intact produced normal qualities and thresholds of pain (42.8 +/- 3.4 and 24.4 +/- 6.2 degrees C for heat and cold pain, respectively). No spatial summation of pricking pain was observed, in contrast to the marked summation of heat pain in normal areas. In areas with only a single intact thermal modality, the quality of the perceived non-painful sensation was not determined by the thermal stimulus but by the intact modality (paradoxical sensation). Cold stimuli were perceived as warm in areas in which only warm sensation was preserved, and vice versa. A similar pattern was also seen for pain perception in areas with intact warm sensation. In these areas, both noxious heat and cold elicited a sensation of heat pain. No consistent pattern of heat-elicited pain was observed in areas in which only cold sensation was intact. These data suggest that the integrity of non-noxious thermal systems is essential for the normal perception of thermal pain, and that the subjective sensation of pain depends on the integration of information from nociceptive and non-nociceptive channels.

Vanilloid receptor homologue, VRL1, is expressed by both A- and C-fiber sensory neurons.

The capsaicin receptor (VR1) homologue, VRL1, is thought to be responsible for transducing high-threshold heat responses in Adelta-fiber neurons. In the present study, the expression of VRL1 by A- or C-fiber sensory neurons in rats was investigated by using a VRL1 and 200 kDa neurofilament (NF200, an A-fiber marker) double immunohistochemical staining method. Approximately 46% of VRL-positive neurons were NF200 positive. Though double-labeled neurons tended to be medium to large, many VRL1 single-labeled neurons were large. Dense VRL1 immunoreactivity was also found in laminae I and II of the spinal dorsal horn, where nociceptive Adelta- and C-fibers normally terminate. These results suggest that both C-fiber and Adelta-fiber primary sensory neurons express VRL1, and VRL1 may play an important role in nociception.

A new method to increase nociception specificity of the human blink reflex

Objective: The medullary R2 response of the blink reflex can be elicited by innocuous and noxious stimuli. The purpose of this study was to elicit a nociception specific R2 response with a new surface electrode.Methods: In 10 healthy subjects the blink reflex was elicited using a standard (10–15 mA) and a new concentric surface electrode type (0.6–1.6 mA) which produces a pin-prick-like pain.Results: After topical local anaesthesia with lignocaine/prilocaine R1 was unchanged, R2 was attenuated by 12% after standard stimulation but was almost abolished (−91%) with the new electrode type.Conclusion: Stimulation with low stimulus intensities but electrode-dependent high current density allows preferential depolarization of superficial nociceptive A-delta fibres. This new method is less traumatic than others and is useful in the study of trigeminal nociception.

Update on the Neurophysiology of Pain Transmission and Modulation: Focus on the NMDA-Receptor

Pain is detected by two different types of peripheral nociceptor neurons, C-fiber nociceptors with slowly conducting unmyelinated axons, and A-delta nociceptors with thinly myelinated axons. During inflammation, nociceptors become sensitized, discharge spontaneously, and produce ongoing pain. Prolonged firing of C-fiber nociceptors causes release of glutamate which acts on N-methyl- d-aspartate (NMDA) receptors in the spinal cord. Activation of NMDA receptors causes the spinal cord neuron to become more responsive to all of its inputs, resulting in central sensitization. NMDA-receptor antagonists, such as dextromethorphan, can suppress central sensitization in experimental animals. NMDA-receptor activation not only increases the cell's response to pain stimuli, it also decreases neuronal sensitivity to opioid receptor agonists. In addition to preventing central sensitization, co-administration of NMDA-receptor antagonists with an opioid may prevent tolerance to opioid analgesia.

Some new insights into the effects of opioids in phasic and tonic nociceptive tests

In this review we critically appraise the value of some phasic and tonic nociceptive tests as models for differentiating the antinociceptive effects of opioid agonists. Using heat-evoked withdrawal of the hind paw or tail of a rodent, several early studies have assessed the effects of stimulus intensity upon antinociceptive potency of opioid agonists. After intrathecal (i.t.) administration of either morphine or sufentanil, for example, for any incremental change in stimulus intensity, the degree of right shift in the dose-response relationship was greater for morphine than for sufentanil. At first glance, such data appear to provide robust support for the pharmacological model of fractional receptor occupancy (FRO), which, according to the historical tenets of classical receptor theory, describes the relationship between intrinsic efficacy and the total receptor concentration. However, new data which elegantly characterize the relative contribution of small calibre unmyelinated and myelinated nociceptive afferents in mediating thermal-evoked responses challenge the exclusivity of such explanations with origins in classical theory. Within our review we report the results of experiments which provide direct electrophysiological evidence that noxious skin heating at a low rate activates C-polymodal nociceptors, but does not effectively activate A-delta mechanothermal nociceptors. In contrast, a high rate of skin heating activates both nociceptor classes, but produces a more intense activation of A-delta nociceptors that occurs after a shorter onset latency compared with the activation of C-fibre nociceptors. Thus, in direct challenge to the traditional model of FRO, a shift in the dose-response relationship of morphine to the right with a reduction in efficacy, may reflect the limited effectiveness of morphine to attenuate the A-delta-mediated component which assumes increasing dominance at high intensity heating. In our appraisal of other nociceptive models we provide an in-depth characterization of afferent processing in the early neonate rat, in which opioids have been tested in both phasic (tail flick and hot-plate) and tonic (formalin) tests. Afferent processing in this model is typified by several behavioural, anatomical and functional features which, although not pathological, are characteristic of those observed in models of nerve injury using the adult rat. Notably, these features include a lack of segmental inhibition (`disinhibition') and afferent input in large diameter myelinated fibres which make synaptic contacts within superficial laminae of the dorsal horn that in the adult are predominantly nociceptive. Paradoxically, because this paradigm demonstrates increased sensitivity to the antinociceptive effects of opioids it may have special merit as a model of tonic pain. It was recently announced that the i.t. administration of pertussis toxin (PTX) caused hyperalgesia and allodynia that appears similar to the symptoms reported by patients suffering from neuropathic pain. Unlike the effects of other opioids so far tested, buprenorphine-induced antinociception is not blocked in this model. This is an exciting finding and provides new optimism that some opioids, notably buprenorphine, may have a special role in managing some types of neuropathic pain.

Non-painful and painful stimulation of human skin and muscle: analysis of cerebral evoked potentials

The present study compared the cerebral processing of non-painful and painful cutaneous CO 2 laser stimulation and intramuscular electrical stimulation in 11 normal subjects. The overall wave form morphology of the long-latency evoked potentials (EPs) at the central vertex (Cz) was identical and surface topographic mappings of the 21-channel recordings showed similar distributions, suggesting involvement of common neural generators. However, the EPs caused by intramuscular stimulation differed from cutaneous stimulation in several distinct ways. First, the latency of the major positive and negative components were significantly shorter with intramuscular stimulation (N 128–145 ms; P 274–298 ms) compared to cutaneous stimulation (N 235–286 ms; P 371–383 ms) ( P<0.001). Second, the peak-to-peak amplitude and root-mean-square values of intramuscular EPs recorded at Cz showed a ceiling effect in the painful range, whereas the laser EPs continued to increase in this range. Third, painful intramuscular, but not non-painful, stimulation caused a frontal activity which not was observed with cutaneous laser stimulation at any intensity. Conduction velocity measurements indicated activation of nociceptive A-delta afferents with cutaneous laser stimulation (10.2±0.2 m/s) and activation of a mixed nerve fiber population with intramuscular electrical stimulation (65.8±25.8 m/s). Differences between laser and intramuscular EPs may be due to different types and origins of activated afferent fibers. Laser EPs can be used specifically to assess cutaneous A-delta fiber function, whereas intramuscular EPs reflect the cerebral processing of a mixed afferent input from muscle tissue.

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)