ReviewAβ-fiber nociceptive primary afferent neurons: a review of incidence and properties in relation to other afferent A-fiber neurons in mammals
Introduction
Nociceptors are distinguished by their relatively high thresholds for activation, i.e. they can be activated by intense stimuli that are damaging (noxious) or potentially damaging to the tissues, but not by innocuous stimuli, such as warming or touch; their adequate stimulus is noxious [59]. Thus nociceptive primary afferent neurons have been defined as having receptive endings that have a high stimulus threshold and that respond preferentially to noxious (tissue-threatening, subjectively painful) stimuli [8] or more simply as units that uniquely signal stimuli intense enough to cause damage to the tissue [42]. Despite the fact that the earliest descriptions of A-fiber nociceptive neurons included units conducting in the Aβ conduction velocity (CV) range, there is a widespread belief, endorsed by many or most modern textbooks even including certain chapters in the Textbook of Pain, e.g. Ref. [18], that nociceptors have only C- or Aδ-fibers and that all Aα/β-fiber afferents are low threshold mechanoreceptors (LTMs). Here, we review the evidence, and provide further evidence, that a substantial proportion of A-fiber nociceptors conduct in the Aβ CV range. The issue of the presence and role of Aβ nociceptors has not previously been reviewed in any detail, although aspects of their electrophysiological properties have been addressed recently in a brief review (see Ref. [36]). We also compare the electrophysiological, cytochemical and sensory receptive properties of Aβ and Aδ nociceptors and of Aβ nociceptors with Aα/β-fiber LTM neurones.
Primary afferent dorsal root ganglion (DRG) neurons are usually divided on the basis of their CVs into C-, Aδ- and Aα/β-fibers (cutaneous afferents) or into group IV, III, II and I fibers (muscle afferents) [42]. Such classes were originally derived from compound action potentials, with the fastest Aα/β/group I wave being carried by large myelinated fibers, the slowest being the C/group IV wave carried by unmyelinated fibers, and the wave carried by small myelinated afferent fibers being the Aδ/group III wave (see Ref. [52]). For references and compound action potential recording methods, see Ref. [14].
Extracellular recordings of compound action potential usually reveal three distinct groups of waves, Aα/β, Aδ and C waves, that can be distinguished on the basis of their electrical thresholds and CVs. The compound action potential shape is dependent on proportions of fiber types in different nerves. In purely afferent nerves such as dorsal roots, the Aα/β wave is dominated by LTMs, since these are more numerous than Aα/β nociceptors, although it is less clear whether D hair (Aδ LTM) units (see later for definition) or Aδ nociceptors dominate the Aδ wave. The contribution from each would depend on (a) their relative frequencies and (b) the stimulus strength used to generate the CAP, since nociceptors may have higher thresholds than D hair units. The relative frequencies of fiber types can vary according to species and nerve type. For example, 80% of Aδ units are D hair units in adult cat posterior femoral cutaneous nerve [4] but we find this value to be only 16% in both guinea pig and rat lumbosacral DRGs.
For comparison between species of CV ranges of Aδ and Aβ-fiber nociceptors, we have plotted in Fig. 1, CV distributions of A-fiber nociceptors and some types of A-fiber LTM units recorded in the same nerves or ganglia. Fig. 1A, B and C are replotted from published papers, and D, E and F are from this laboratory. In A–E the vertical dotted line indicates the upper end of the main body of the D hair range excluding occasional outliers with faster CVs. In A and B this was 30 m/s and was used as the upper end of the Aδ CV range [4]. In rat and guinea pig (Fig. 1D and E) this line is co-incident with the mean value for upper end of the Aδ wave of the dorsal root compound action potential in adult rat (6.4 m/s, n=4 ([19]) and young adult guinea pig (4.2 m/s, n=10 ([16]), an example of compound action potential recording is shown in Fig. 1F. This confirms that the upper border of the main part of the D hair CV range can indeed provide a good indication of the upper end of the Aδ CV range as originally suggested by the cat studies [4]. Following this approach, the upper value for the Aδ range in the mouse study would be 7 m/s, although 10 m/s was chosen [33]. However, using the fastest D hair (nearly 10 m/s) to define the border in that study in which a wide range of ages was used (5–32 weeks), is likely to overestimate the Aδ/Aβ border for all but the oldest animals. The lower values for guinea pig (and slightly lower for rat) than for mouse reflect the younger ages (see Table 1), and that these were dorsal root recordings made at 30 °C. Further details of Aδ upper borderlines defined in papers that examine A-fiber nociceptive CVs are provided in Table 1 with information on species, nerve, temperature and age/weight of the animals where available.
Many factors may influence CVs including species, age/size, the nerve type, the temperature of the preparation, and whether or not utilisation time (see below) is excluded. To amplify these points, examples of the effects of species are shown in Table 1, and Fig. 1. CVs of myelinated afferent fibers increase substantially with age up to 300 days [3], [57] and CV and body weight increase simultaneously during the rapid growth of young animals [3]. The velocity of conduction along afferent A fibers may slow towards the periphery [26]. The CV of the rat sciatic nerve (peak CV of A-fibers) varied about 1.2 m/s per degree centigrade over the range of 20–40 °C [3]. A Q10 of approximately 1.6 in the temperature range of 27–37 °C was reported for mammalian myelinated nerves (see Ref. [69]). Fibers of the same neurons conduct more slowly in the dorsal root than the peripheral nerve [68]. The utilisation time is the time taken for an AP to be generated after application of an electrical stimulus and unless excluded it causes a reduction in the calculated CV, creating a proportionately greater error when the latency is short [68]. Thus failure to exclude utilisation time causes an error (underestimate) of CV that is likely to be greater for faster conducting fibers especially in smaller animals with short conduction distances. All these factors mean that the borderlines between the CV ranges need to be directly determined, e.g. by compound action potential recordings or D hair CV range in animals of the same age and species, on the same segment of nerve, at the same temperature, and using the same stimulus methods. Inappropriate classifications do commonly occur, however. For instance, the upper limits of 30 m/s for Aδ-fibers appropriate for adult cat peripheral nerve (Fig. 1 [42] are sometimes erroneously applied to rat studies).
CVs of A-fiber nociceptors have been reported as extending up to 65 m/s in cat [4], [5] and up to 70 m/s in monkey [65], clearly including units with Aβ-fibers since in both species the Aδ range was only up to 30 m/s (see Fig. 1). Thus the presence of A-fiber nociceptive units with CVs in the Aβ range is apparent in the earliest studies of A-fiber nociceptors [4], [5] (data replotted in Fig. 1A and B) and is also a consistent finding in other species including guinea pig, rat and mouse (Fig. 1 and Table 1). As can be seen in Table 1 and Fig. 1, the proportion of recorded nociceptive A-fiber units conducting in the Aβ CV range is consistently relatively high (ranging from 18% to 65%) in different species.
The lack of clear peaks of Aδ and Aβ CVs in the CV frequency distribution of A-fiber nociceptors leads to the appearance of a single unimodal distribution across the A-fiber CV range (Fig. 1). This might be one of the reasons for Aβ-fiber nociceptors having been largely ignored, and raises the question of whether they are functionally distinct from Aδ nociceptors. The shape of the CV distribution of all A-fiber nociceptors is skewed with a peak towards the upper end of the Aδ (D hair) range or at the Aδ/Aβ border (e.g. guinea pig and rat, Fig. 1D,E) and with a long tail projecting into the CV range of the faster conducting cutaneous LTM units, usually reaching about half way along the extent of Aαβ range or even further in some species (e.g. Fig. 1D, rat). Thus it is clear, in a variety of species, that there are nociceptive A-fiber neurons that conduct in a range defined as Aβ either by compound action potential measurements or by comparison with Aδ (D hair) LTM units. Because few of these fibers have CVs in the upper Aαβ CV range, we and others call them Aβ-fiber nociceptors, while the fast conducting LTMs are said to have Aα/β-fibers.
Section snippets
Soma size in relation to sensory properties
It is frequently stated that small DRG neurons are slowly conducting C-fiber nociceptors and large neurons are LTMs with Aα/β-fibers. Although slowly conducting neurons tend to be small, there is considerable overlap in cell size among DRG neurons with C-, Aδ- and Aα/β-fibers [26]. A higher proportion of C- than Aδ- and of Aδ- than of Aα/β-fiber DRG neurons are nociceptive, with the result that a higher proportion of small than of large neurons is nociceptive. Thus, while small size indicates a
Nociceptive neurons
Many nociceptive neurons respond to more than one of the following stimulus modalities: noxious mechanical, noxious thermal and noxious chemical (e.g. Refs. [2], [4]). However, many studies on receptive properties of primary afferent neurons, including the early studies [2], [4], use only heat and mechanical stimuli. The nociceptive units that respond to both these types of stimulus are called mechano-heat (MH) sensitive units. Consequently the terms CMH and AMH are often used to refer to
Non-nociceptive A-fiber neurons
Broadly speaking, non-nociceptive neurons can be divided into low threshold thermoreceptive (cool and warm receptive) and low threshold mechanoreceptive (LTM) neurons. However, most non-nociceptive afferent DRG neurons projecting to skin and skeletal muscle are LTMs. Cutaneous LTMs conduct in all CV ranges (Aα/β-, Aδ- and C-fiber CV), and muscle afferent LTMs conduct in group I and group II ranges. Experimentally, LTMs are identified in vivo by their responses to non-noxious mechanical stimuli
Electrophysiological membrane properties of A-fiber DRG neurons
The membrane properties of DRG neurons are often examined with intracellular recordings from their somata not only because such recordings are difficult to make from the terminals, but also because there are some similarities between the properties of the cell bodies (soma) and their terminals [25]. Electrophysiological recordings show that DRG neurons are heterogeneous in their afferent CVs, receptive properties and their somatic AP configuration. Some neurons exhibit APs with inflections on
Cytochemical properties of A-fiber DRG neurons
Although immunocytochemical studies carried out on unidentified DRG neurons have provided valuable information on differential expression of several molecules (e.g. peptides, proteins, enzymes, receptors) in different subgroups (different sizes) of DRG neurons, there have been only few studies, mostly from this laboratory, relating specific molecular expression to particular sensory properties in identified neurons. Such studies involves intracellular recording in DRG neurons in vivo and
Central projections
In addition to electrophysiological differences between nociceptive and LTM neurons, these two groups have distinct central projections. They show generally non-overlapping termination in the dorsal horn of adult spinal cord, with Aδ-nociceptive neurons projecting to both superficial (lamina I and IIo (outer lamina II) and deeper laminae (lamina V), whereas A-fiber LTMs terminate deep in superficial laminae (IIi-V) (for review, see Ref. [22]). Recent studies have shown that neonatal LTMs
A-fiber neurons and pain
Activation of nociceptors usually results in pain once the nociceptive information reaches the appropriate centres of the brain in a conscious animal.
Conclusions
In this review we present clear evidence for the existence in a number of species of nociceptive primary afferent neurons conducting in the Aβ CV range. Indeed, the percentage of A-fiber nociceptors that conduct in the Aβ range is about 50% in rodents, and in rat the percentage of Aαβ-fiber neurons that is nociceptive is about 20%. Thus Aβ nociceptors are a substantial population that should no longer be ignored. Aβ nociceptors differ from Aδ nociceptors in showing a less extreme form of
Acknowledgments
This work was supported by Wellcome Trust UK and BBSRC grants to SNL. Thanks to C. Berry and B. Carruthers for technical assistance.
References (75)
- et al.
Latency to detection of first pain
Brain Res.
(1983) - et al.
Differences in the size of the somatic action potential overshoot between nociceptive and non-nociceptive dorsal root ganglion neurones in the guinea-pig
Neuroscience
(2001) - et al.
Increased conduction velocity of nociceptive primary afferent neurons during unilateral hindlimb inflammation in the anaesthetised guinea-pig
Neuroscience
(2001) - et al.
Binding sites for the plant lectin Bandeiraea simplicifolia I-isolectin B(4) are expressed by nociceptive primary sensory neurones
Brain Res.
(2001) - et al.
A key to the classification of cutaneous mechanoreceptors
J. Invest. Dermatol.
(1977) - et al.
Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury
Pain
(2000) - et al.
Primary afferent units from the hairy skin of the rat hind limb
Brain Res.
(1982) - et al.
Lack of involvement of capsaicin-sensitive primary afferents in nerve-ligation injury induced tactile allodynia in rats
Pain
(1999) - et al.
Aging effects on conduction velocities of myelinated and unmyelinated fibers of peripheral nerves
Neurosci. Lett.
(1985) - et al.
Tackling pain at the source: new ideas about nociceptors
Neuron
(1998)
Key role of the dorsal root ganglion in neuropathic tactile hypersensibility
Eur. J. Pain
Impaired pressure sensation in mice lacking TRPV4
J. Biol. Chem.
Conduction velocity changes along the processes of rat primary sensory neurons
Neuroscience
Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: electrophysiological evidence
Pain
The Trk family of neurotrophin receptors
J. Neurobiol.
Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli
J. Neurophysiol.
Age changes in conduction velocity, refractory period, number of fibres, connective tissue space and blood vessels in sciatic nerve of rats
J. Comp. Neurol.
Myelinated afferent fibres responding specifically to noxious stimulation of the skin
J. Physiol.
Receptor types in cat hairy skin supplied by myelinated fibers
J. Neurophysiol.
Sensitization of unmyelinated nociceptive afferents in monkey varies with skin type
J. Neurophysiol.
Peripheral neuronal mechanisms of nociception
A capsaicin-receptor homologue with a high threshold for noxious heat
Nature
Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain
J. Neurosci.
Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey
J. Neurophysiol.
Pathophysiology of damaged nerves in relation to chronic pain
Association of somatic action potential shape with sensory receptive properties in guinea pig dorsal root ganglion neurons
J. Physiol.
The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons
J. Physiol.
Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Na(v)1.7 (PN1) Na+ channel alpha subunit protein
J. Physiol.
The dorsal horn: state dependent processing, plasticity and the generation of pain
The presence and role of the tetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptive primary afferent neurons
J. Neurosci.
TrkA expression and IB4 binding in functionally identified dorsal root ganglion (DRG) nociceptive neurones in rats in vivo
J. Physiol.
The sensitization of high threshold mechanoreceptors with myelinated axons by repeated heating
J. Physiol.
Laminar organisation of primary afferent terminations in the mammalian spinal cord
Mechanical response properties of nociceptors innervating feline hairy skin
J. Neurophysiol.
Similarities between some properties of the soma and sensory receptors of primary afferent neurones
Exp. Physiol.
Conduction velocity is related to morphological cell type in rat dorsal root ganglia
J. Physiol.
Electrical properties of rat dorsal root ganglion neurones with different peripheral conduction velocities
J. Physiol.
Cited by (280)
Dorsal Root Ganglion Stimulation for Chronic Groin Pain: A Review
2022, NeuromodulationDorsal Root Ganglion Stimulation for Chronic Pain: Hypothesized Mechanisms of Action
2022, Journal of PainSelective neural inhibition via photobiomodulation alleviates behavioral hypersensitivity associated with small sensory fiber activation
2024, Lasers in Surgery and Medicine