Pain is an unpleasant sensation localized to a part of the body. It is often described in terms of a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Furthermore, any pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. These properties illustrate the duality of pain: it is both sensation and emotion. When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction if often present.


The Pain Sensory System – The Anatomy

The nervous system has two anatomical divisions: the central nervous system (CNS) and the peripheral nervous system (PNS). CNS consists of the brain and the spinal cord, whereas PNS includes spinal nerves, their roots, and branches; cranial nerves and their branches; and components of the autonomic nervous system (ANS).

Collections of nerve cell bodies in the CNS form nuclei, meanwhile those in PNS form ganglia. Ganglia and nuclei contain either motor or sensory neurons.

Spinal Nerves

Spinal nerves are attached to the spinal cord. They transmit both motor and sensory impulses and are, thus, considered mixed nerves. Most cranial nerves are attached to the brain, of which some are either motor or sensory only, while others are mixed.

The spinal cord is composed of segments, as indicated by the 31 pairs of spinal nerves. Each segment has numerous dorsal and ventral rootlets that arise from the respective surfaces of the spinal cord and these respective rootlets unite to form dorsal and ventral roots. Dorsal rootlets contain neuronal processes that conduct afferent impulses to the spinal cord, whereas the ventral rootlets conduct efferent impulses from the spinal cord.

The dorsal root contains the central processes of sensory neuronal cell bodies that are located in the dorsal root ganglion (DRG). The peripheral processes of these sensory neuronal cell bodies are located in the spinal nerve, its rami, and their branches. These processes end at or form receptors. The ventral root contains motor fibers. Their neuronal cell bodies are found in the gray matter of the spinal cord: ventral horn if the axons innervate skeletal muscle; lateral horn if the axons supply smooth muscle, cardiac muscle, or glands.

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After that, the dorsal and ventral roots join to form a short, mixed spinal nerve. Almost immediately after its formation, the spinal nerve divides into mixed dorsal and ventral rami. Among them, the dorsal rami supply intrinsic (deep) muscles of the back and neck, joints of the vertebral column, and skin on the dorsal surface of the trunk, neck, and head. Ventral rami innervate all other muscles of the neck and trunk (including the diaphragm), skin of the anterior and lateral body walls, and all muscles, and skin of the limbs. Therefore in general, ventral rami are larger than dorsal rami.

Dermatomes

All spinal nerves, with the exception of C1, transmit sensory information from the skin. Most of the skin of the face and scalp is supplied by the trigeminal nerve (one of  12 pairs of cranial nerves).

Cranial Nerves

There are 12 pairs of cranial nerves. The spinal part of CN XI takes origin from upper cervical spinal cord, enters the cranial cavity through foramen magnum and, in the jugular foramen, joins a cranial root from the brain stem. CN II-XII are attached to the brain stem. Cranial nevers are sensory, motor, or mixed.

Autonomic Nervous System

Autonomic Nervous System (ANS) is functional divided rather than anatomic divided. Autonomic nervous system and somatic motor system consist make up the motor (efferent) portion of the PNS.

The ANS has sympathetic, parasympathetic, and enteric (ENS/Enteric Nervous System) divisions. The ENS is a network of neurons located within the wall of the gastrointestinal tract. This part of the ANS can function autonomously, although it interacts with the sympathetic and parasympathetic divisions. Somatic efferent impulses utilize a single neuron to transmit information from the CNS to skeletal muscle. In contrast, sympathetic and parasympathetic efferent information is transmitted through two neurons.

Visceral Afferent fiber conduct sensory information (pain or reflexive) from organs to the CNS. Their neuronal cell bodies are located either in dorsal root ganglia or a sensory ganglion associated with CN IX and X. They are considered part of the ANS, but not classified as sympathetic or parasympathetic.

Adrenal Medulla is unique in that it “acts” as the ganglion. The chromatin cells of the adrenal medulla are equivalent to postganglionic sympathetic neutrons. Upon stimulation by preganglionic sympathetic axons, they release neurotransmitters (epinephrine and norepinephrine) directly into the circulation.


How The Pain Generates?

The stimuli that activate pain receptors vary from one tissue to another. The adequate stimulus for skin is one that has the potential to injure tissue, i.e., pricking, cutting, crushing, burning, and freezing. These stimuli are ineffective when applied to the stomach and intestine, where pain is produced by an engorged of inflamed mucosa, distention or spasm of smooth muscle, and traction on the mesenteric attachment. In skeletal muscle, pain is caused by ischemia, necrosis, hemorrhage, and injection of irritating solutions as well as by injuries of connective tissue sheaths. Prolonged contraction of skeletal muscle evokes an aching type of pain. Ischemia is also the most important cause of pain i cardiac muscle. Joints are insensitive to pricking, cutting, and cautery, but pain can be produced in the synovial membrane by inflammation and by exposure to hypertonic saline. The stretching and tearing of ligaments around a joint can evoke severe pain. Injuries to the periosteum give rise to pain but probably not to other sensation. Blood vessels are a source of pain when pierced by a needle or involved in an inflammatory process. Distention of arteries or veins, as occurs with thrombotic or embolic occlusion, may be sources of pain; other mechanisms of headache relate to traction on arteries or inflammation to he meningeal structures by which they are supported. Pain from intraneural lesions probably arises from the sheaths of the nerves. Nerve root(s) and sensory ganglia, when compressed, give rise to pain.


Pain and The Sensitization

Heuristically, pain can be divided into several distinct sets of events, including acute nociception, tissue injury, nerve injury, and the affective dimensions. Primary afferents are classified by their diameter, degree of myelination, and conduction velocity. The largest-diameter afferent fibers, Aβ, respond maximally to light touch and/or moving stimuli. They are present primarily in nerves that innervate the skin. In normal individuals, the activity of these fibers dose not produce pain. There are two other classes of primary afferents: the small-diameter myelinated Aδ and the unmyelinated C fiber axons. These fibers are present in nerves to the skin and to deep somatic and visceral structures.

The acute activation of Aδ and C fibers generates transient input into the spinal cord, which in turn leads to activation of neurons that project contralaterally to the thalamus and thence to the somatosensory cortex. Besides, a parallel spinofugal projection is to the medial thalamus and from there to the anterior cingulate cortex, part of the limbic system.

PS: Ascending Pathway for Pain. A majority of spinal neurons contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons form the contralateral spinothalamic tract, which lies in the contralateral anterolateral white matter of the spinal cord (where the change from one side to the other starts), the lateral edge of the medulla, and the lateral pons and midbrain.

When Aδ fibers are activated, glutamate is released as the neurotransmitter and pain is produced immediately. This type of pain is called first pain, or fast pain/epicritic pain, which is a rapid response and mediates the discriminative aspect of pain or the ability to localize the site and intensity of the noxious stimulus.

Activation of C fibers, which release a combination of glutamate and substance P, is responsible for the delayed second pain (also called slow pain or protopathic pain) which is the dull, intense, diffuse, and unpleasant feeling associated with a noxious stimulus. Itch and tickle are also related to pain sensation.

Molecular Mechanism of Pain

On the organizations and tissues on the endings of nociceptive sensory nerves that respond to noxious thermal, mechanical, or chemical stimuli, there are distribution of a variety of receptors. Many of these are part of a family of nonselective cation channels called transient receptor potential (TRP) channels. This includes TRPV1 receptors (the V refers to a group of chemicals called vanilloids) that are activated by intense heat, acid, and chemicals such as capsaicin. TRPV1 receptors can also be activated indirectly by initial activation of TRPV3 receptors in keratinocytes in the skin.

Noxious mechanical, cold, and chemical stimuli may activate TRPA1 receptors (A, for ankyrin) on sensory nerve terminals. Acid sensing ion channel (ASIC) receptors are activated by pH changes within a physiological range and may be the dominant receptors mediating acid-induced pain.

Purinergic receptors (P2X, an ionotropic receptor, P2Y, an a G protein-coupled receptor) are activated by indirect stimuli. For example, some nociceptive stimuli release intermediate molecules like ATP, etc, and these intermediate molecules then activate purinergic receptors. Another example is the tyrosine receptor kinase A (TrkA), which is activated by nerve growth factor (NGF) that is released as a result of tissue damage.

Itch and tickle can be produced by repeated local mechanical stimulation of the skin, also, a variety of chemical agents including histamine and kinins such as bradykinin, which are released in the skin in response to tissue damage, can produce itch and tickle. Kinins exert their effects by activation of two types of G protein-coupled receptor, B1 and B2. At present we know that the activation of bradykinin B2 receptors is a downstream event in protease-activated receptor-2 (PAR-2) activation, which induce both a nociceptive and a pruritogenic response.

PS: pain-producing substances include histamine, prostaglandins, serotonin, kinins, potassium ions, hight H+, and others.

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Sensitization

Following tissue injury or local inflammation (e.g., local skin burn, toothache, rheumatoid joint, etc.), an ongoing pain state arises that is characterized by burning, throbbing, or aching and an abnormal pain response. This abnormal pain response is called hyperalgesia, or the sensitization, which can be divided into peripheral sensitization and central sensitization. Peripheral sensitization is the results of some active factors such as substance P, prostaglandins, bradykinin, cytokines, H+ ions, and so on. When these substances are released into the injury site, they have the ability to activate the terminal of small high-threshold afferents (Aδ and C fibers) and to reduce the stimulus intensity required to activate these sensory afferents. In addition, the ongoing afferent traffic initiated by the injury leads to the activation of spinal facilitatory cascades, enhancing the excitability of nerve cells in the dorsal horn of the spinal corda and yielding a greater output to the brain for any given input. This facilitation is thought to underlie the hyperalgesic states, which we called it the central sensitization. The pain caused by sensitization usually is called the “nociceptive” pain.

Injury to the peripheral nerve yields complex anatomical and biochemical changes in the nerve and spinal cord that induce spontaneous dysesthesia. This nerve injury pain state may not depend upon the activation of small afferents, but may be initiated by low-threshold sensory afferents like Aβ fibers. Such nerve injuries result in the development of ectopic activity arising from neuromas formed by nerve injury and the dorsal root ganglia of the injured axons as well as a dorsal horn reorganization, such that low-threshold afferent input carried by Aβ fibers evokes a pain state. This dorsal horn reorganization reflects changes in ongoing inhibition and in the excitability of dorsal horn projection neurons. Note that this kind of pain is typically considered to respond less well to opioid analgesics.

Emotional effect

Interestingly, painful stimuli have the certain ability to generate strong emotional components that reflect a distinction between pain as a specific sensation subserved by distinct neurophysiological structures, and pain such as suffering (the original sensation plus the reactions evoked by the sensation, the affective motivational dimension). When pain does not evoke its usual responses such as anxiety, fear, panic, and suffering, a patient’s ability to tolerate the pain may be markedly increased, even when the capacity to perceive the sensation is relatively unaltered.

Besides, a tickling sensation or itch usually is regarded as pleasurable. And the simple scratching relieves itching because it activates large, fast-conducting afferents that gate transmission in the dorsal horn in a manner analogous to the inhibition of pain by stimulation of similar afferents.

Referred Pain

The fundamentals of referred pain is that the axon of each primary afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many primary afferents. The convergence of sensory inputs to a single spinal pain transmission neuron is of great importance because it underlies the phenomenon of referred pain. All spinal neurons that receive input from the viscera and deep musculoskeletal structures also receive input from the skin.

The convergence patterns are determined by the spinal segment of the dorsal root ganglion that supplies the afferent innervation of a structure. For example, the afferents that supply the central diaphragm are derived from the third and fourth cervical dorsal root ganglia. Primary afferents with cell bodies in these same ganglia supply the skin of the shoulder and lower neck. Thus, sensory inputs from both the shoulder skin and the central diaphragm converge on pain-transmission neurons in the third and fourth cervical spinal segments.

Because of this convergence and the fact that the spinal neurons are most often activated by inputs from the skin, activity evoked in spinal neurons by input from deep structures is mislocalized by the patient to a place that roughly corresponds with the region of skin innervated by the same spinal segment.