Synonyms

Nociceptive Temporomandibular Joint Afferents; Nociceptive Masseter Muscle Afferents

Definition

Primary afferent fibers that innervate the temporomandibular joint (TMJ) and masticatory muscles, and are activated by noxious mechanical, chemical or thermal stimuli applied to these tissues. These afferent fibers transduce and convey information about potential or actual tissue injury from the orofacial region to the central nervous system.

Characteristics

TMJ Nociceptors

The TMJ is innervated by thinly myelinated and unmyelinated afferent fibers, with non-specialized endings, which contain clear and dense core vesicles. This suggests some of these afferent fibers release neurotransmitters and neuropeptides, such as calcitonin gene related peptide (CGRP) and substance P, from their terminal endings (Kido et al. 1995). These small-diameter afferent fibers project, via the gasserian or trigeminal ganglion, to the trigeminal subnuclei interpolaris and caudalis (Casatti et al. 1999; Capra 1987; Widenfalk and Wiberg 1990), areas of the caudal brainstem which appear to be most important for the integration of nociceptive input from deep orofacial tissues. Electrophysiological studies have confirmed the projection of a subpopulation of TMJ afferent fibres with conduction velocities of less than 25 m/sec (Aδ and C fibres) to the caudal brainstem (Cairns et al. 2001 a,b). These fibres are activated by noxious mechanical and/or chemical stimuli and appear to function as nociceptors (Cairns et al. 2001 a,b).

TMJ afferent fibers, identified as mechanical nociceptors by their response to noxious protrusion or lateral movement of the TMJ, have been described (Cairns et al. 2001a; Loughner B et al. 1997). These fibers are not activated by innocuous jaw opening, but begin to discharge as lateral rotation of the jaw exceeds the normal range, and exhibit a progressively increased discharge with supra-normal rotation of the jaw. Some of these nociceptors also appear to encode rate of jaw rotation (Loughner B et al. 1997). The threshold of TMJ nociceptors to noxious mechanical rotation of the jaw is lower in females than males; however, this is apparently due to sex-related differences in the biomechanical properties of the TMJ tissues (Loughner B et al. 1997).

TMJ nociceptors respond to injection of algogenic substances such as mustard oil, potassium chloride and glutamate into the TMJ, which also evokes a nociceptive reflex response in the jaw muscles (Cairns et al. 2001a; Cairns et al. 1998) The activity of TMJ nociceptors precedes, but has a markedly shorter duration, than reflex jaw muscle activity evoked by injection of glutamate into the TMJ. This finding has led to the speculation that a brief activation of TMJ nociceptors, by algogenic compounds such as glutamate, is sufficient to induce central sensitization, a period of prolonged increase in the excitability of trigeminal subnucleus caudalis neurons (Cairns et al. 2001a). Such a phenomenon may explain the diffuse referral pattern of TMJ pain, which may spread to include the masticatory and neck muscles, and why acute joint pain can sometimes significantly outlast the duration of nociceptive stimulation.

Sex-related differences in the chemical response characteristics of TMJ nociceptors have also been noted. The greatest response to algogenic compounds has been observed in small, mechanically sensitive afferent fibers with conduction velocities of less than 10 m/s, which suggests that these particular fibers function as polymodal nociceptors, i.e. nociceptors that respond to more than one type of noxious stimulation. Sex-related differences in response to injection of glutamate into the TMJ have been best characterized. Injection of glutamate into the TMJ has been found to evoke significantly greater nociceptive reflex responses and discharge in polymodal nociceptors in females than in males (Cairns et al. 2001a) Such sex-related differences in TMJ nociceptor excitability may explain, in part, the increased prevalence of certain orofacial pain syndromes in women (Dao and LeResche 2000).

Algogenic compounds, such as mustard oil and glutamate, excite TMJ nociceptors in part through activation of peripheral NMDA and non-NMDA receptors (Cairns et al. 1998). This suggests that peripheral glutamate receptor antagonists may be of use in modifying the excitability of TMJ nociceptors under certain pathological conditions. In contrast, the peripheral endings of TMJ nociceptors are not excited by γ-aminobutyric acid (GABA), which is thought to depolarize the central endings of nociceptors (Cairns et al. 2001a). Indeed, the current evidence suggests that GABA may in fact decrease the excitability of TMJ nociceptors through activation of peripheral GABAA receptors (Cairns et al. 1999). This unexpected effect of GABA suggests that the activation of peripheral GABAA receptors may result in a local analgesia of the TMJ.

Masseter Muscle Nociceptors

Anatomical and electrophysiological studies have indicated that the masseter muscle is also innervated by thinly myelinated and unmyelinated trigeminal afferent fibers with non-specialized endings, which project to the trigeminal subnucleus interpolaris and caudalis (Cairns et al. 2002; Cairns et al. 2001b; Cairns et al. 2003; Capra and Wax 1989; Nishimori et al. 1986) These fibers are activated by noxious mechanical and/or chemical stimuli and appear to function as nociceptors (Cairns et al. 2002; Cairns et al. 2001b; Cairns et al. 2003).

About one-third of masseter muscle afferent fibers that project to subnucleus caudalis have mechanical thresholds that exceed the human pressure pain threshold (Cairns et al. 2003; Svensson et al. 2003). In uninjured masseter muscle, these nociceptors are predominantly Aδ fibers with conduction velocities of less than 10 m/sec (Cairns et al. 2002; Cairns et al. 2003). Most of these nociceptors exhibit slowly adapting responses to sustained noxious mechanical stimulation (Fig. 1). A significant sex-related difference in the mechanical threshold of these nociceptors has not been found.

Figure 1
figure _1_978-3-540-29805-2_2793

Examples of deep orofacial tissue nociceptor response characteristics. (a) The line drawing illustrates antidromic action potentials (*), evoked by electrical stimulation of the caudal brainstem, to confirm the central projection target of these masseter muscle Aδ nociceptors. (b) Sustained noxious mechanical stimulation of the masseter muscle with an electronic Von Frey hair (lower trace), resulted in a slowly adapting discharge (upper trace). (c) The peri-stimulus histograms illustrate the effect of injection of the algogenic substance glutamate into the masseter muscle. Note that glutamate-evoked nociceptor discharge was markedly greater in the female than in the male.

Full size image

Like TMJ nociceptors (see above), masseter muscle mechanical nociceptors also respond to the injection of algogenic substances such as hypertonic saline and glutamate, but not GABA, into their mechanoreceptive field (Cairns et al. 2002; Cairns et al. 2001; Cairns et al. 2003). The afferent discharge evoked by these algongenic substances is greatest in C fibers and in Aδ fibers with conduction velocities of less than 10 m/s. Thus, these particular fibers appear to function as polymodal nociceptors.

Glutamate consistently evokes significantly greater nociceptor discharges and pain responses in females than in males (Cairns et al. 2002; Cairns et al. 2001; Cairns et al. 2003) (see examples, Fig. 1). Thus, sex-related differences in masseter muscle nociceptor excitability appear to underlie, at least in part, the increased prevalence of masticatory muscle pain conditions suffered by women (Dao and LeResche 2000). Prolonged mechanical sensitization of the masseter muscle and its nociceptors has also been demonstrated to occur after injection of glutamate into the masseter muscle, although there do not appear to be sex-related differences in this phenomenon (Cairns et al. 2002; Svensson et al. 2003).

Unlike TMJ nociceptors, current evidence suggests that glutamate-evoked afferent discharge in masseter nociceptors is predominantly mediated through activation of peripheral NMDA receptors (Cairns et al. 2003). Glutamate-induced mechanical sensitization is also mediated through activation of peripheral glutamate receptors (Cairns et al. 2002). Thus, peripheral NMDA receptor antagonists may prove to be particularly effective analgesics for the treatment of masticatory muscle pain.

Conclusion

The role of orofacial nociceptors is to transduce and convey information about the intensity and quality of orofacial pain. The characteristics of TMJ and masseter muscle nociceptors suggest that they may play a role not only in the development, but also in the maintenance of certain types of orofacial pain, and contribution to sex differences in TMJ and masticatory muscle pain.