**2. Pain classification: physiology and physiopathology of orofacial pain**

Nociceptive impulses generated by potential or actual tissue damage are just one of the types of input that are continually assessed and evaluated throughout the various levels within the central nervous system (CNS). Nociception provides the brain a chance to interpret pains and make behavioral adjustments to avoid further potential damaging stimuli [1].

*First-order nociceptive neurons*, whether they synapse in the spinal trigeminal nucleus or in the dorsal horn, excite the same type of second-order neurons that respond to nociceptive signals as well as a variety of sensory stimuli and are therefore called wide-dynamic range neurons. These neurons conduct nociception and other sensations through the brainstem and display varying degrees of arborization with structures throughout the reticular formation, where baseline physiologic processes are controlled before reaching the third-order neurons in the thalamus [2–5]. *Second-order neurons*, stimulated by the faster conducting A-delta fibers, arborize less than those receiving impulses from the slower conducting C-fibers. While the A-delta fibers release glutamate during this process, the C-fibers release a wide variety of neurotransmitters [6, 7]. The available information about the conduction velocity helps us to establish a connection between A-delta fibers and acute pain and between C-fibers and chronic pain.

*Third-order circuits*, which start in the thalamus and connect the sensory cortex with the basal ganglia and the limbic system, interpret nociceptive input [2, 8]. However, sometimes the pain source is difficult to locate even when pain is felt. For example, the cutaneous stimuli are easier to recognize than the stimuli from visceral organs and muscles just because dermis has much more free nerve endings. In response to pain interpretation, multilevel behavioral responses are coordinated, and descending motor commands are created. Whether nociception is delivered to the CNS through the spinothalamic tract or the trigeminal thalamic tract, pain perception evokes autonomic nervous system (ANS)-modulated cranial nerve responses [2, 9, 10].

Pain in the head and face often involves activation of the trigeminal ganglion nerves and the development of peripheral and central sensitization. The symptoms could be acute-like in toothache or chronic-like in migraine or temporomandibular disorders (TMD).

More important than a single nerve pathway, the expression "trigeminal system" alludes to a really complex course of action of, interneurons, nerve transmission fibers, and synaptic connection which process approaching information from the three divisions of the trigeminal nerve. This nerve is in fact a blended nerve containing both sensory and motor fibers. While sensory fibers innervate the face, conjunctiva, mucous membranes of the oral and nasal cavities, teeth, conjunctiva, dura mater of the brain, and intracranial and extracranial blood vessels, motor fibers support mostly the masseter, temporalis, and the other mastication muscles. Primary afferent neurons carry out sensory information from the face and mouth (except nociception) through trigeminal ganglion. The trigeminal-brain stem complex is the place where a synapse with a second-order neuron occurs. This complex receives simultaneously afferent axons from the upper cervical (C2, C3), vagus, glossopharyngeal and nerves and afferent input primarily from the trigeminal nerve (facial pain and headaches may be a consequence of this connection between the upper cervical nerves and the trigeminal spinal tract nucleus).

**87**

**interaction**

*Sleep and Orofacial Pain: Physiological Interactions and Clinical Management*

We can separate the trigeminal-brain stem sensory nuclear complex in two different structures: the trigeminal main sensory nucleus and the trigeminal spinal tract nucleus, also known as the nucleus of the descending tract of cranial nerve V [11]. The spinal tract nucleus is structured of three separate nuclei going from a rostral (superior) to caudal (inferior) direction: subnucleus oralis, subnucleus interpolaris, and subnucleus caudalis. Subnucleus caudalis is situated in the medulla, in some cases, stretching out to the dimension of C2 or C3 and it is the most important brain relay site of nociceptive information emerging from the orofacial area. Because the nucleus caudalis is anatomically continuous with, and structurally similar to, the spinal cord dorsal horn, and because it extends into the medulla as well, it is often referred to as the medullary dorsal horn [12]. Descending nerve fibers from higher levels of the CNS or medication can change or modulate incoming nociceptive signals to the subnucleus caudalis and projecting nociceptive signals on their way to

Inflammation and peripheral tissue injury increase the interaction between neuronal cell bodies and satellite glial cells within the trigeminal ganglion [13]. These interactions have been shown to play an important role in the induction and maintenance of peripheral sensitization of trigeminal nociceptive neurons. Under normal conditions, neuron-glia interactions in the trigeminal ganglia are involved in information processing, neuroprotection, and regulation of neuronal activity including the basal rate of spontaneous firing and threshold of activation to maintain homeostasis. While a transient increase in neuron-glia communication is associated with an acute response to inflammatory signals, stable gap junctions are formed between trigeminal neurons and satellite glia in response to sustained

Astrocytes, which are specialized glial cells, and the most abundantly found cells in the CNS, perform similar functions to satellite glia [15]. This means that they facilitate the regulation of neuronal development, synaptic coupling, repair, and even nutritional support. On the other hand, astrocytes can monitor and control the concentration of ions, neurotransmitters, and metabolites, as well as water movement, and thus play a key role in modulating the excitability state of neurons both in the brain and the spinal cord [16]. Microglia, other important glial cells present in the CNS, act as immune cells to remove cellular debris and dead cells; they also release inflammatory mediators to promote healing [17, 18]. Glial cells are responsible for regulating the extracellular environment around neurons and hence neuronal activities, and their importance in regard to the underlying pathology of many inflammatory diseases is gradually becoming recognized. Therefore, they have emerged as important cellular targets for therapeutic intervention given their role in promoting peripheral and central sensitiza-

*DOI: http://dx.doi.org/10.5772/intechopen.86770*

inflammation that is implicated in TMD's [14].

**3. Pathophysiological aspects of sleep-pain interaction**

Understanding pathophysiological mechanisms of sleep-pain interaction requires first of all to be aware that some of those influences attributed to sleep could be in fact related to circadian modulation of both pain and sleep mechanisms.

**3.1 Relationship between circadian timing system, sleep, and pain: a cyclic** 

The circadian timing system is a complex neurophysiological network comprising a central biological clock, usually called the master pacemaker and several peripheral

tion and persistent pain [19].

the thalamus.

#### *Sleep and Orofacial Pain: Physiological Interactions and Clinical Management DOI: http://dx.doi.org/10.5772/intechopen.86770*

We can separate the trigeminal-brain stem sensory nuclear complex in two different structures: the trigeminal main sensory nucleus and the trigeminal spinal tract nucleus, also known as the nucleus of the descending tract of cranial nerve V [11]. The spinal tract nucleus is structured of three separate nuclei going from a rostral (superior) to caudal (inferior) direction: subnucleus oralis, subnucleus interpolaris, and subnucleus caudalis. Subnucleus caudalis is situated in the medulla, in some cases, stretching out to the dimension of C2 or C3 and it is the most important brain relay site of nociceptive information emerging from the orofacial area. Because the nucleus caudalis is anatomically continuous with, and structurally similar to, the spinal cord dorsal horn, and because it extends into the medulla as well, it is often referred to as the medullary dorsal horn [12]. Descending nerve fibers from higher levels of the CNS or medication can change or modulate incoming nociceptive signals to the subnucleus caudalis and projecting nociceptive signals on their way to the thalamus.

Inflammation and peripheral tissue injury increase the interaction between neuronal cell bodies and satellite glial cells within the trigeminal ganglion [13]. These interactions have been shown to play an important role in the induction and maintenance of peripheral sensitization of trigeminal nociceptive neurons. Under normal conditions, neuron-glia interactions in the trigeminal ganglia are involved in information processing, neuroprotection, and regulation of neuronal activity including the basal rate of spontaneous firing and threshold of activation to maintain homeostasis. While a transient increase in neuron-glia communication is associated with an acute response to inflammatory signals, stable gap junctions are formed between trigeminal neurons and satellite glia in response to sustained inflammation that is implicated in TMD's [14].

Astrocytes, which are specialized glial cells, and the most abundantly found cells in the CNS, perform similar functions to satellite glia [15]. This means that they facilitate the regulation of neuronal development, synaptic coupling, repair, and even nutritional support. On the other hand, astrocytes can monitor and control the concentration of ions, neurotransmitters, and metabolites, as well as water movement, and thus play a key role in modulating the excitability state of neurons both in the brain and the spinal cord [16]. Microglia, other important glial cells present in the CNS, act as immune cells to remove cellular debris and dead cells; they also release inflammatory mediators to promote healing [17, 18]. Glial cells are responsible for regulating the extracellular environment around neurons and hence neuronal activities, and their importance in regard to the underlying pathology of many inflammatory diseases is gradually becoming recognized. Therefore, they have emerged as important cellular targets for therapeutic intervention given their role in promoting peripheral and central sensitization and persistent pain [19].
