Nalini Vadivelu, Amarender Vadivelu and Alan David Kaye (eds.)Orofacial Pain2014A Clinician’s Guide10.1007/978-3-319-01875-1_1
© Springer International Publishing Switzerland 2014 2014
1. The Neurobiology of Orofacial Pain
Nalini Vadivelu1 , Yili Huang2 , Peter Mancini2, Shaun Gruenbaum2, Amarender Vadivelu3 and Susan Dabu-Bondoc2, 4
(1)
Department of Anesthesiology, Yale University School of Medicine and Yale-New Haven Hospital, 333 Cedar Street, 208051, New Haven, CT 06520-8051, USA
(2)
Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, 208051, New Haven, CT 06520-8051, USA
(3)
Annoor Dental College and Hospital, Muvattupuzha, Kerala, 686673, India
(4)
Haven Hospital, 333 Cedar Street, 208051, New Haven, CT 06520-8051, USA
Abstract
Orofacial pain is a significant and costly health issue that leads to severe psychological, emotional, social, and economic stresses, estimated to have a financial burden of $6 billion annually in the USA alone. Because the orofacial area holds such special significance in daily actions such as eating, drinking, speech, and sexual behavior, pain in that region is especially debilitating. There have been numerous recent advances in the understanding of the neurobiology of orofacial pain. This chapter details the unique neurologic pathway of orofacial pain from the primary afferent nociceptors that generate the pain to the central relay within the brainstem and cerebral cortex that receives it as well as the important biochemical influences by which the pain is modulated. Finally, the neurobiology and key aspects of two of the most common and perplexing orofacial syndromes, neuropathic orofacial pain and pain due to temporomandibular dysfunction, are elucidated. While temporomandibular dysfunction is associated with a complex multifactorial etiology, neuropathic orofacial pain can be further differentiated into trigeminal neuropathic pain, atypical facial pain, and chronic facial pain; each has its own unique pathophysiology. A thorough understanding of all of these aspects of the neurobiology of orofacial pain is essential to the clinical diagnosis and treatment of this costly and debilitating condition.
Introduction
Pain is a health issue that affects many Americans. It is estimated that $6 billion is spent annually in the treatment of pain in the USA [1]. Pain disorders cause severe psychological, emotional, and social stresses and may interfere with activities of daily living and sleep, thereby perpetuating a vicious cycle of pain and social dysfunction.
The orofacial area holds special significance in daily actions such as eating, drinking, speech, and sexual behavior, and pain in that region is especially debilitating. The area is also richly innervated, and the influx of such sensations may be the reason why so many people find going to the dentist unpleasant [2]. There have been numerous recent advances in the understanding of the unique pathophysiology of orofacial pain, and this chapter details both neurologic pathways in which the pain is generated as well as the biochemical modalities by which the pain is modulated. Finally, the neurobiology and key aspects of neuropathic orofacial pain and pain due to temporomandibular dysfunction, two of the most perplexing orofacial syndromes, are also discussed.
Primary Afferent Nociceptor
There are three different types of primary peripheral afferents. Aβ fibers are myelinated and thick, allowing the Aβ fibers to be the fastest conducting fibers. Aδ fibers have thinner, myelinated axons and are slower than Aβ fibers. Finally, C fibers are the thinnest and unmyelinated, making C fibers the slowest fibers for conductance [3].
The orofacial region is mainly innervated by the trigeminal nerve, whose primary afferent cell bodies rest within the trigeminal ganglion. These neurons generally possess type Aδ or C fibers [4]. While the fast type Aβ fibers are activated via light touch and pressure, the slower Aδ and C fibers of the trigeminal region, collectively termed nociceptors, respond to pain. The activation of these two types of nociceptors is associated with substantial release of substance P, which modulates pain sensitivity by the activation of neurokinin-1 receptors [5].
These nociceptors can be further subdivided into mechanonociceptors (sensitive to mechanical stimuli), thermo-nociceptors (sensitive to heat or cold), and chemo-nociceptors (sensitive to chemicals). The thermo-nociceptors are found to possess vanilloid receptor 1-like receptors that contribute to the pain caused by extreme temperatures [6]. Similarly, the mechanoreceptors found in the root pulp are lined with epithelial Na+ channels that are responsible for sharp pain induced by liquid motion in the dentinal tubules [7].
Modulation to these nociceptors can also be mechanical or chemical in nature. Canine studies have demonstrated that the threshold for mechanonociception can be lower with periodontal inflammation and can thus increase sensitization [8]. This may be due to the hydrodynamic mechanism of inflammation in the noncompliant environment of the dentine-encased pulp, which increases the pressure on the pulp and thereby activates the nociceptors [9]. Furthermore, there is considerable peripheral and central modulation due to the many types of neuropeptides released during tissue damage and localized within the trigeminal ganglia. These peptides, such as substance P and calcitonin-related peptide, play a vital role in sensitizing the nociceptors leading to allodynia (pain to innocuous stimuli) and hyperalgesia (increased response to painful stimuli) [10].
Finally, unlike the spinal system, where damage of a peripheral nerve causes hypersensitivity to noxious stimuli of nearby skin, nerve damage and territorial hypersensitivity of the trigeminal spinal nucleus are much less predictable [11]. Transection of the inferior alveolar nerve induces hypersensitivity of the trigeminal neurons in the upper lip, outside the territory of the inferior alveolar nerve [12]. A possible explanation of this phenomenon may have to do with the uniquely different central relay of the trigeminal system.
Central Relay
In the brainstem, the primary afferent neurons terminate at the trigeminal spinal tract nucleus. This nucleus consists of three subnuclei: subnucleus oralis, subnucleus interpolaris, and subnucleus caudalis. The subnucleus caudalis serves as the main brainstem relay for nociception and is so structurally similar to the spinal dorsal horn, an important structure in spinal nociception, that it is often referred to as the trigeminal dorsal horn [13]. The subnucleus caudalis or the trigeminal dorsal horn is an important central structure for the modulation of nociception. Rat studies have suggested that disinhibition of the trigeminal subnucleus caudalis plays a major role in the appearance of allodynia after nerve damage [14]. Inflammation or trauma induces a central sensitization of the subnucleus caudalis through its afferent nociceptors via various physiologic and biochemical mechanisms such as ion channels, neurokinins, and N-methyl-d-aspartate (NMDA). This increases the excitability of the subnucleus and leads to allodynia, hyperalgesia, or even spontaneous pain. Conversely, descending inhibitory modulation, found mainly in the dorsomedial fields, occurs via behavioral or environmental triggers and can be a contributing mechanism in the efficacy of certain analgesics such as morphine and tricyclic antidepressants [15].
Although the other two subnuclei of the trigeminal spinal tract nucleus, the subnucleus oralis and subnucleus interpolaris, receive input from all three types of fiber, it receives a large proportion of input from fast-conducting Aβ fibers. This makes these subnuclei very versatile. Central neurons within these subnuclei can be further classified into nociceptive specific neurons, which are only Aδ and C fibers responding only to noxious stimuli, or wide dynamic range neurons, consisting of all three fiber types and responding to noxious and innocuous stimuli [16]. Deep pain is attributed to the convergence of different types of receptors into a central nociceptive neuron; the complexity of the convergences leads to misinterpretation of the original sensation, which contributes to hyperalgesia or allodynia [17]. Additional studies also indicate that the transition zone between the subnuclei caudalis and the subnuclei interpolaris also plays a role in the central processing of deep orofacial nociception [18].
Orofacial sensation continues up its path from the brainstem through the thalamus on its way to the cortex. Nociceptive specific neurons and wide dynamic range neurons are found scattered throughout the thalamus including the posterior nucleus, ventrobasal complex or ventral posterior nucleus, and intralaminar nucleus. The posterior nucleus is responsible for classifying a stimulus as pain, the ventrobasal complex or the ventral posterior nucleus localizes the pain to a region, and the intralaminar nucleus provides an affective and motivational dimension to the pain. In other words, the lateral thalamus projects to the somatosensory cerebral cortex to pinpoint the pain, while the medial thalamus projects to other areas such as the cingulate gyrus and hypothalamus to associate the pain with the proper emotions [19].
Biochemical Influences
Biochemical influences play a large role in the transmission and modulation of orofacial pain. Recent studies have focused on various biochemical neuroactive substances and proteins such as nitric oxide (NO), nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH), GABA, glycine, and c-Fos and their roles in orofacial pain modulation.
Neurons within the subnucleus oralis and subnucleus caudalis produce nitric oxide, a substance that increases intracellular cyclic guanosine monophosphate levels to work as both an endothelial relaxing factor as well as a neurotransmitter [20]. Increased levels of nitric oxide have been associated with neuropathic pain associated with NMDA receptor stimulation [21]. Surprisingly, while NO is also associated with the maintenance of chronic pain, it has no association to the initiation of acute pain [22].
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