Several acute and chronic pain conditions in the face or mouth are very common, and some are unique to the orofacial region. However, the etiology and pathogenesis of most orofacial chronic pain conditions are unresolved, and they are difficult to diagnose and manage. This article provides a brief overview of the neural mechanisms underlying orofacial pain and then highlights recent findings indicating that nonneural cells, specifically satellite cells in the sensory ganglia and astroglia and microglia cells in the central nervous system, are important players in both acute and chronic inflammatory and neuropathic orofacial pain conditions and may offer new targets for management of these conditions.

Growing evidence suggests that astroglia are involved in pain states, but no studies have tested their possible involvement in modulating the activity of nociceptive neurons per se. This study has demonstrated that the central sensitization induced in functionally identified nociceptive neurons in trigeminal subnucleus caudalis (the medullary dorsal horn) by application of an inflammatory irritant to the rat's tooth pulp can be significantly attenuated by continuous intrathecal superfusion of methionine sulfoximine (MSO; 0.1 mm), an inhibitor of the astroglial enzyme glutamine synthetase that is involved in the glutamate–glutamine shuttle. Simultaneous superfusion of MSO and glutamine (0.25 mm) restored the irritant-induced central sensitization. In control experiments, superfusion of either MSO or glutamine alone, or vehicle, did not produce any significant changes in neuronal properties. These findings suggest that the astroglial glutamate–glutamine shuttle is essential for the initiation of inflammation-induced central sensitization but that inhibition of astroglial function may not affect normal nociceptive processing.

Chronic orofacial pain conditions can be particularly difficult to diagnose and treat because of their complexity and limited understanding of the mechanisms underlying their aetiology and pathogenesis. Furthermore, there is considerable variability between individuals in their susceptibility to risk factors predisposing them to the development and maintenance of chronic pain as well as in their expression of chronic pain features such as allodynia, hyperalgesia and extraterritorial sensory spread. The variability suggests that genetic as well as environmental factors may contribute to the development and maintenance of chronic orofacial pain. This article reviews these features of chronic orofacial pain, and outlines findings from studies in animal models of the behavioural characteristics and underlying mechanisms related to the development and maintenance of chronic orofacial pain and trigeminal neuropathic pain in particular. The review also considers the role of environmental and especially genetic factors in these models, focussing on findings of differences between animal strains in the features and underlying mechanisms of chronic pain. These findings are not only relevant to understanding underlying mechanisms and the variability between patients in the development, expression and maintenance of chronic orofacial pain, but also underscore the importance for considering the strain of the animal to model and explore chronic orofacial pain processes.

Background: It has been reported that the P2Y₁₂receptor (P2Y₁₂R) is involved in satellite glial cells (SGCs) activation, indicating that P2Y₁₂R expressed in SGCs may play functional roles in orofacial neuropathic pain mechanisms. However, the involvement of P2Y₁₂R in orofacial neuropathic pain mechanisms is still unknown. We therefore studied the reflex to noxious mechanical or heat stimulation of the tongue, P2Y₁₂R and glial fibrillary acidic protein (GFAP) immunohistochemistries in the trigeminal ganglion (TG) in a rat model of unilateral lingual nerve crush (LNC) to evaluate role of P2Y₁₂R in SGC in lingual neuropathic pain.Results: The head-withdrawal reflex thresholds to mechanical and heat stimulation of the lateral tongue were significantly decreased in LNC-rats compared to sham-rats. These nocifensive effects were apparent on day 1 after LNC and lasted for 17 days. On days 3, 9, 15 and 21 after LNC, the mean relative number of TG neurons encircled with GFAP-immunoreactive (IR) cells significantly increased in the ophthalmic, maxillary and mandibular branch regions of TG. On day 3 after LNC, P2Y₁₂R expression occurred in GFAP-IR cells but not neuronal nuclei (NeuN)-IR cells (i.e. neurons) in TG. After 3 days of successive administration of the P2Y₁₂R antagonist MRS2395 into TG in LNC-rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly decreased coincident with a significant reversal of the lowered head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue compared to vehicle-injected rats. Furthermore, after 3 days of successive administration of the P2YR agonist 2-MeSADP into the TG in naïve rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly increased and head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue were significantly decreased in a dose-dependent manner compared to vehicle-injected rats.Conclusions: The present findings provide the first evidence that the activation of P2Y₁₂R in SGCs of TG following lingual nerve injury is involved in the enhancement of TG neuron activity and nocifensive reflex behavior, resulting in neuropathic pain in the tongue.

The extracellular activity of single neurons was recorded in subnucleus caudalis (medullary dorsal horn) of chloralose-anesthetized cats to test the effects of electrical and natural stimuli that activated afferents supplying the jaw and tongue muscles as well as the face, teeth, and intraoral mucosa. Many caudalis neurons that could be functionally classified on the basis of their cutaneous receptive-field properties as low-threshold mechanoreceptive (LTM), wide-dynamic-range (WDR), or nociceptive-specific (NS) neurons could be excited by muscle afferent stimuli. Only five neurons were encountered that received muscle afferent inputs and had no demonstrable cutaneous, dental, or mucosal input. The muscle afferent inputs were a particular feature of the cutaneous nociceptive (i.e., WDR and NS) neurons. Approximately two-thirds of this nociceptive neuronal population (n = 109) could be excited by jaw and/or tongue muscle stimulation, whereas only a small proportion of the LTM neuronal population (n = 247) was activated by muscle afferent stimulation. Neurons with a demonstrated direct axonal projection to the contralateral thalamus as well as nonprojection neurons received muscle afferent inputs. The caudalis nociceptive neurons receiving muscle as well as cutaneous afferent inputs had receptive-field properties comparable to those previously described for caudalis cutaneous nociceptive neurons; they were predominantly located in laminae I/II and V/VI, and many also received convergence of tooth pulp afferent inputs. These neurons generally had larger cutaneous receptive fields than neurons unresponsive to muscle afferent stimulation. The muscle afferent inputs were considered to be predominantly of a nociceptive character for several reasons. These included the long latency and high threshold of most neuronal responses evoked by electrical stimulation of the muscle afferents, the predominance of afferents of small diameter in some of the muscle nerves stimulated, the preferential responsiveness to the muscle afferent stimulation of neurons that were functionally identified as cutaneous nociceptive neurons, and the responsiveness of most of the neurons excited by electrical stimulation of the muscle nerves also to noxious mechanical or thermal stimulation of muscle and the injection of two or more algesic chemicals into small arteries supplying the jaw and tongue muscles. Of the algesic chemicals used in this study (7% NaCl, KCl, bradykinin, histamine, 5-HT), the first two were found to be the most effective and to cause the most rapidly induced excitation.(ABSTRACT TRUNCATED AT 400 WORDS)