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

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

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

potential damaging stimuli [1].

to an increased pain intensity and a reduction of pain tolerance. A vicious cycle can then be perpetuated, and therefore an adequate knowledge on the sleep-pain interaction-related mechanisms should be an important part of learning and training in the domain of clinical sleep neurology, which is in the scope of this book.

**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

*First-order nociceptive neurons*, whether they synapse in the spinal trigeminal nucleus

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).

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

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disorders (TMD).

oscillators, also known as peripheral clocks. The human master clock corresponds to a group of neurons located in the anterior part of the hypothalamus above the optic chiasm named the suprachiasmatic nucleus (SCN). Peripheral clocks are virtually present in all cells of the body. This time-related machinery dictates what we may consider an internal time which regulates almost all body functions in a 24-h periodic fashion. The Latin term "circadian" means circa-diem, about 1 day or 24 h, and this is because our clocks are adapted to the geophysical routine of the natural day-night cycle divided in the precise 24-h period of social time [20]. Both the period of human natural circadian rhythm and the sleep-wake cycle are not exactly 24 h but a little bit longer (more or less 24.6 h) consequently, a kind of hit on the clock should occur every day in order to get our body synchronized with social time. That is one of the main functions of melatonin, an hormone which is secreted in response to the absence of light and suppressed when light is present. The basic mechanism involves the activation or inhibition of photoreceptors in the eye's retina which activate/ stop taking melanopsin to the suprachiasmatic nucleus stimulating or inhibiting melatonin secretion. Although mediated by these retinal ganglionic cell-related photoreceptors, the rods and cones also have photic inputs to SCN. Peripheral clocks within each cell have a mechanism which is identical to the clocks found in the SCNisolated neurons. However, although in isolation each cell is time-autonomous, they tend to generate a single circadian pattern dictated by SCN when these SCN neuronal population couple with other cells via humoral and non-humoral pathways [21, 22].

For biological clocks to be successful, they should accurately keep time and adjust to environmental signals. This requires adequate coupling between the SCN and peripheral clocks. In the absence of SCN signaling, peripheral clocks become desynchronized. As there is a tissue-specific time control that is in part locally controlled, loss of synchronization usually propagates and disturbs the circadian rhythm of such tissue as it was shown to occur in the liver [23–25] as well as in other tissues and organs within the human body.

#### **3.2 The circadian regulation of pain**

Some important features of pain are regulated by the circadian timing system. For instance, pain sensitivity follows a rhythmic cycle modulated by the 24 h biological clocks. However, it remains unclear whether rhythmicity is derived from daily oscillations within the underlying causes driving the pain or from rhythmic oscillatory component of the neural processing of pain. Pain-related rhythmic influences, however seem to be independent of either subjective or objective responses suggesting that its modulation occurs on a basic physiological level. Interestingly, this 24 h related pain modulatory mechanism is also dependent of pain intensity which in turn affects pain sensitivity in such a manner that the more intense the pain is, the greater the change in its sensitivity across the day. On the other hand, the particular type of pain seems relevant for the clinical impact of its circadian modulation. A recent prototype of human daily pain sensitivity curve was proposed (**Figure 1**).

#### **3.3 Pain regulation by the homeostatic sleep drive**

The sleep-wake cycle is the most conspicuous circadian rhythm in humans with a clear relationship with night (dark)-day (light) oscillation. Actually, sleep is itself regulated by a dual process comprising a circadian component and homeostatic one. This model presented by Borbely explains that we may predict a better sleep when it occurs at night and when we are tired compared to diurnal sleep and/or when we are full of energy.

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**components**

*their variation during the 24 h of social day.*

**Figure 1.**

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

The daily rhythm of pain sensitivity is affected not only by circadian rhythmicity, but also by sleep-related homeostatic drive. Actually, either acute and chronic pain are correlated with sleep duration and sleep quality, but while results from distinct basic studies point to a specific modulation of sleep with a wide range of results, there is a lack of human experiments to consolidate clinical knowledge. For instance, even with standardized protocols, there are significant variations in the

*Prototypical human "daily pain sensitivity" curve (adapted from [31]), the graphic illustrates the circadian profile of pain sensitivity to different pain modalities (thermic: heat and cold, electrical, and nociceptive) and* 

**3.4 Neural pathways for pain are regulated by both circadian and homeostatic** 

The dorsal root ganglia have a circadian rhythmicity since clock genes—those genes generating a near 24 h rhythm—are expressed there. The role of circadian regulation of the neural circuitry underlying pain also involves the rhythmic expression of genes that facilitate synaptic transmission as calcium channel subunits and NMDA glutamate receptor subunits [27]. On the other hand, there are some studies showing that the majority of afferents in this route are nociceptors,

Painful stimuli and non-noxious mechanical sensitivity are differently modulated by the human circadian system since mechanical sensitivity peaks in the late afternoon (15–18 h); whereas, pain sensitivity peaks in the middle of the night (0–3 am). There is also a circadian component on inhibition of pain processing in the dorsal horn. It is however unclear what part of this inhibitory control is from the circadian machinery or dependent of the sleep homeostatic drive, since sleep deprivation is known to affect the higher levels of pain processing. Interestingly, pharmacological agents that copy that top-down inhibitory control such as morphine are ineffective after severe sleep deprivation [29, 30] and there is evidence suggesting a neutral response of fast pain processing in case of sleep deprivation. On the other

thus suggesting that the circadian pattern is of nociceptive origin [27, 28].

results [26] which make interpretation sometimes difficult.

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

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

#### **Figure 1.**

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

tissues and organs within the human body.

**3.3 Pain regulation by the homeostatic sleep drive**

**3.2 The circadian regulation of pain**

oscillators, also known as peripheral clocks. The human master clock corresponds to a group of neurons located in the anterior part of the hypothalamus above the optic chiasm named the suprachiasmatic nucleus (SCN). Peripheral clocks are virtually present in all cells of the body. This time-related machinery dictates what we may consider an internal time which regulates almost all body functions in a 24-h periodic fashion. The Latin term "circadian" means circa-diem, about 1 day or 24 h, and this is because our clocks are adapted to the geophysical routine of the natural day-night cycle divided in the precise 24-h period of social time [20]. Both the period of human natural circadian rhythm and the sleep-wake cycle are not exactly 24 h but a little bit longer (more or less 24.6 h) consequently, a kind of hit on the clock should occur every day in order to get our body synchronized with social time. That is one of the main functions of melatonin, an hormone which is secreted in response to the absence of light and suppressed when light is present. The basic mechanism involves the activation or inhibition of photoreceptors in the eye's retina which activate/ stop taking melanopsin to the suprachiasmatic nucleus stimulating or inhibiting melatonin secretion. Although mediated by these retinal ganglionic cell-related photoreceptors, the rods and cones also have photic inputs to SCN. Peripheral clocks within each cell have a mechanism which is identical to the clocks found in the SCNisolated neurons. However, although in isolation each cell is time-autonomous, they tend to generate a single circadian pattern dictated by SCN when these SCN neuronal population couple with other cells via humoral and non-humoral pathways [21, 22]. For biological clocks to be successful, they should accurately keep time and adjust to environmental signals. This requires adequate coupling between the SCN and peripheral clocks. In the absence of SCN signaling, peripheral clocks become desynchronized. As there is a tissue-specific time control that is in part locally controlled, loss of synchronization usually propagates and disturbs the circadian rhythm of such tissue as it was shown to occur in the liver [23–25] as well as in other

Some important features of pain are regulated by the circadian timing system.

The sleep-wake cycle is the most conspicuous circadian rhythm in humans with a clear relationship with night (dark)-day (light) oscillation. Actually, sleep is itself regulated by a dual process comprising a circadian component and homeostatic one. This model presented by Borbely explains that we may predict a better sleep when it occurs at night and when we are tired compared to diurnal sleep and/or when we are

For instance, pain sensitivity follows a rhythmic cycle modulated by the 24 h biological clocks. However, it remains unclear whether rhythmicity is derived from daily oscillations within the underlying causes driving the pain or from rhythmic oscillatory component of the neural processing of pain. Pain-related rhythmic influences, however seem to be independent of either subjective or objective responses suggesting that its modulation occurs on a basic physiological level. Interestingly, this 24 h related pain modulatory mechanism is also dependent of pain intensity which in turn affects pain sensitivity in such a manner that the more intense the pain is, the greater the change in its sensitivity across the day. On the other hand, the particular type of pain seems relevant for the clinical impact of its circadian modulation. A recent prototype of human daily pain sensitivity curve was

**88**

full of energy.

proposed (**Figure 1**).

*Prototypical human "daily pain sensitivity" curve (adapted from [31]), the graphic illustrates the circadian profile of pain sensitivity to different pain modalities (thermic: heat and cold, electrical, and nociceptive) and their variation during the 24 h of social day.*

The daily rhythm of pain sensitivity is affected not only by circadian rhythmicity, but also by sleep-related homeostatic drive. Actually, either acute and chronic pain are correlated with sleep duration and sleep quality, but while results from distinct basic studies point to a specific modulation of sleep with a wide range of results, there is a lack of human experiments to consolidate clinical knowledge. For instance, even with standardized protocols, there are significant variations in the results [26] which make interpretation sometimes difficult.

### **3.4 Neural pathways for pain are regulated by both circadian and homeostatic components**

The dorsal root ganglia have a circadian rhythmicity since clock genes—those genes generating a near 24 h rhythm—are expressed there. The role of circadian regulation of the neural circuitry underlying pain also involves the rhythmic expression of genes that facilitate synaptic transmission as calcium channel subunits and NMDA glutamate receptor subunits [27]. On the other hand, there are some studies showing that the majority of afferents in this route are nociceptors, thus suggesting that the circadian pattern is of nociceptive origin [27, 28].

Painful stimuli and non-noxious mechanical sensitivity are differently modulated by the human circadian system since mechanical sensitivity peaks in the late afternoon (15–18 h); whereas, pain sensitivity peaks in the middle of the night (0–3 am). There is also a circadian component on inhibition of pain processing in the dorsal horn. It is however unclear what part of this inhibitory control is from the circadian machinery or dependent of the sleep homeostatic drive, since sleep deprivation is known to affect the higher levels of pain processing. Interestingly, pharmacological agents that copy that top-down inhibitory control such as morphine are ineffective after severe sleep deprivation [29, 30] and there is evidence suggesting a neutral response of fast pain processing in case of sleep deprivation. On the other

hand, cortical responses to fast pain also seem to diminish after disturbed sleep. The relative balance of circadian versus homeostatic components in pain processing may depend on the specific type of pain [31].

Although there is still a lack of knowledge on the orofacial pain-sleep interaction, basic and clinical evidence on both acute and chronic pain helps to elucidate the important role of these general components.
