25. Pain Receptors and Pain Pathways

What is the "gate control" theory?

"Gate Control" theory was proposed in the mid 1960s. The concept of the gate control theory is that non-painful input closes the gates to painful input, which results in prevention of the pain sensation from traveling to the CNS (i.e., non-noxious input suppresses pain). The theory suggests that collaterals of the large sensory fibers carrying cutaneous sensory input activate inhibitory interneurons, which inhibit (modulate) pain transmission information carried by the pain fibers. Non-noxious input suppresses pain, or sensory input "closes the gate" to noxious input. The gate theory predicts that at the spinal cord level, non-noxious stimulation will produce presynaptic inhibition on dorsal root nociceptor fibers that synapse on nociceptors spinal neurons (T), and this presynaptic inhibition will block incoming noxious information from reaching the CNS (i.e., will close the gate to incoming noxious information).

What are the four different types of skin nociceptors?

1. High threshold mechanonociceptors or specific nociceptors. They respond to intense mechanical stimulation such as pinching, cutting, or stretcching. 2. Thermal nociceptors: respond to the above stimuli and thermal stimuli. 3. Chemical nociceptors which respond only to chemical substances. 4. Polymodal nociceptors: high intensity stimuli such as mechanical, thermal, and chemical substances.

Describe c fibers (group IV) vs delta fibers (group III).

A delta fibers (group III fibers) are 2-5 mm in diameter, myelinated, have a fast conduction velocity (5-40 meters/sec), and carry information mainly from the nociceptive-mechanical or mechanothermal-specific nociceptors. Their receptive fields are small. Therefore, they provide precise localization of pain. C fibers (group IV fibers) are 0.4-1.2 mm in diameter, unmyelinated, have a slow conduction velocity (0.5-2.0 meters/sec), and are activated by a variety of high-intensity mechanical, chemical and thermal stimulation and carry information from polymodal nociceptors. C-fibers comprise about 70% of all the fibers carrying noxious input. Two classes of C-fibers have been identified. The receptive field of these neurons is large and, therefore, less precise for pain localization. Upon entering the spinal cord, the pain fibers bifurcate and ascend and descend to several segments, forming part of the tract of Lissauer before synapsing on neurons on Rexed layers I to II. In general, nociceptors responding to noxious stimuli transmit the information to the CNS via A delta fibers, which make synaptic connections to neurons in Rexed layer I (nucleus posterior marginalis) and layer V. The nociceptors responding to chemical or thermal stimuli (i.e., the polymodal nociceptors) carry their activity mainly by C unmyelinated fibers. One class of C fibers terminates in Rexed layer I, and the second class terminates in Rexed layer II (substantia gelatinosa). These fibers release substance P, glutamate, aspartate calcitonin gene related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and nitric oxide.

What is allodynia?

Allodynia is pain resulting from a stimulus that does not normally produce pain. For example, light touch to sunburned skin produces pain because nociceptors in the skin have been sensitized as a result of reducing the threshold of the silent nociceptors. Also, when peripheral neurons are damaged, structural changes occur and the damaged neurons reroute and make connection also to sensory receptors (i.e., touch-sensitive fibers reroute and make synaptic connection into areas of the spinal cord that receive input from nociceptors).

Where does cardiac pain get referred to?

Cardiac pain is referred to the left hand. The left hand and the heart are developed from the same myotome and are innervated by the same nerve. Area of referred pain (i.e., pain originating from the gall bladder is referred to the right chest and back).

What is somatic pain?

Cutaneous, Superficial or Peripheral Pain: Pain that arises from the skin and muscles or peripheral nerves themselves. In general, this pain has two components, the initial response followed by later response. These signals are transmitted via different pathways: Pricking pain reaches the CNS via neospinothalamic tract (i.e., LST) to the VPL (or VPM) and to the sensory cortex. Burning and soreness pain resulting from tissue damage reaches the CNS via the paleospinothalamic tract and archispinothalamic tract to brain stem nuclei and to PF-CM complex (of the thalamus). Deep pain: This pain arises from joint receptors tendons and fascia (i.e., deep structures). The quality of deep pain is dull, aching or burning. Deep pain is accompanied by a definite autonomic response associated with sweating and nausea, changes in blood pressure and heart rate. Somatic deep pain reaches the CNS mainly via the paleospinothalamic and archispinothalamic tract

What are the four types of nociceptive neurons in the spinal cord?

High threshold mechanoreceptor neurons or nociceptive specific neurons. These neurons are excited only by noxious cutaneous and/or visceral stimuli. The nociceptive afferent fibers release glutamate and different neuropeptides to activate the dorsal horn neurons. Chemical nociceptor neurons are excited by chemical or thermal noxious stimulus in the skin or in visceral organs. Thermal nociceptor neurons are excited by chemical or thermal noxious stimulus in the skin or in visceral organs. Polymodal-nociceptive neurons or multi, or wide dynamic range nociceptive neurons. These neurons are excited by both noxious and non-noxious cutaneous and/or visceral stimuli (polymodal nociceptive neurons). These neurons are activated by a variety of noxious stimuli (mechanical, thermal, chemical, etc.) and respond incrementally to increasing intensity of the stimuli.

What are the joint nociceptors?

High threshold mechanoreceptors, polymodal nociceptors, and "silent" nociceptors. Many of these fibers innervating these endings in the joint capsule contain neuropeptides, such as substance P and calcitonin gene-related peptide. Liberation of such peptides is believed to play a role in the development of inflammatory arthritis.

What is hyperalgesia?

Hyperalgesia is an increased painful sensation in response to additional noxious stimuli. The threshold for pain in the area surrounding an inflamed or injured site is lowered, and the inflammation activates silent nociceptors and/or the damage elicits ongoing nerve signals (prolong stimulation), which led to long-term changes and sensitized nociceptors. These changes contribute to an amplification of pain or hyperalgesia, as well as an increased persistence of the pain. If one pricks normal skin with a sharp probe, it will elicit sharp pain followed by reddened skin. The reddened skin is an area of hyperalgesia.

What are silent nociceptors?

In the skin and deep tissues there are additional nociceptors called "silent" nociceptors. These receptors are normally unresponsive to noxious mechanical stimulation, but become "awakened" (responsive) to mechanical stimulation during inflammation and after tissue injury. This activation of silent nociceptors may contribute to the induction of hyperalgesia, central sensitization, and allodynia. Activation of the nociceptor initiates the process by which pain is experienced, (e.g., we touch a hot stove or sustain a cut). These receptors relay information to the CNS about the intensity and location of the painful stimulus.

What is visceral pain?

In the visceral organs, nociceptors respond to mechanical stimulation such as pressure, tissue damage, and chemical stimulation. Most noxious information carried by visceral afferents does not give rise to conscious sensation. Visceral pain is diffuse, less precisely graded and typically accompanied by slowing of the heart, lowered blood pressure, cold sweats and nausea. It conveys also hunger, thirst, electrolyte balance, irregulation in the respiratory and circulatory systems. Many of these signals reach the CNS bilaterally by the following three channels: In the visceral organs, free nerve endings are scattered, and any stimulus that excites these nerve endings causes visceral pain. Such stimuli include spasm of the smooth muscle in a hollow viscus, or distention or stretching of the ligament, such as a stone blocking the ureter or the gall ducts. Stretching of the tissues such as intestinal obstruction can also provoke visceral pain. Visceral pain is also caused by chemical means as a result of gastrointestinal lesions, and tumors as well as thrombosis of an artery. In many cases, visceral pain is not localized to the site of its cause, rather in a distant site.

What is referred pain?

Is a painful sensation at a site other than the injured one. The pain is not localized to the site of its cause (visceral organ) but instead is localized to a distant site. One possible explanation is that the axons that carry pain information from the viscera enter into the spinal cord by the same route as the cutaneous pain sensation axons. Within the spinal cord there is a convergence of the information on the same nociceptive spinal cord neurons. This convergence gives rise to the phenomenon of referred pain. For example, pain associated with angina pectoris, or myocardial infarction is referred to the left chest, left shoulder, and upper left arm. Pain resulting from distention of the colon is referred to the periumbilical area

What is neuropathic pain?

Is a sharp, shooting and devastating pain. It is a persistent pain that arises from functional changes occurring in the CNS secondary to peripheral nerve injury. Once the nerve is damaged, the damaged nerve elicits sustained activation of nociceptors and/or nociceptive afferents. The neuropathic pain is due to an abnormal activation of the nociceptive system without specifically stimulating the nociceptors. Neuroplastic changes occurring in the CNS secondary to the afferent barrage are believed to culminate in CNS neuronal hyperexcitability. Many scientists suggest that "sensitization" of the nervous system following injury is a factor in neuropathic pain. Neuropathic pain can usually be controlled by anti-inflammatory drugs and opioids. In some cases, such as in diabetics, AIDS, cancer, etc., no treatment or relief is available to neuropathic pain. Neuropathic pain should not be confused with neurogenic pain, a term used to describe pain resulting from injury to a peripheral nerve but without necessarily implying any neuropathy.

What is the archispinothalamic pathway?

It is a multisynaptic diffuse tract or pathway and is phylogenetically the oldest tract that carries noxious information. The first-order nociceptive neurons make synaptic connections in Rexed layer II (substantia gelatinosa) and ascend to laminae IV to VII. From lamina IV to VII, fibers ascend and descend in the spinal cord via the multisynaptic propriospinal pathway surrounding the grey matter to synapse with cells in the MRF-PAG area. Further multisynaptic diffuse pathways ascend to the intralaminar (IL) areas of the thalamus (i.e., PF-CM complex) and also send collaterals to the hypothalamus and to the limbic system nuclei. These fibers mediate visceral, emotional and autonomic reactions to pain.

What are the three pathways that carry pain sensation?

Neospinal thalamic tract, paleospinal thalamic tract, and archispinal thalamic tract.

What are the different endogenous opioids?

Opioidergic neurotransmission is found throughout the brain and spinal cord and appears to influence many CNS functions, including nociception, cardiovascular functions, thermoregulation, respiration, neuroendocrine functions, neuroimmune functions, food intake, sexual activity, aggressive locomotor behavior as well as learning and memory. Opioids exert marked effects on mood and motivation and produce euphoria. Three classes of opioid receptors have been identified: μ-mu, δ-delta, κ-kappa All three classes are widely distributed in the brain and found to be members of the G protein receptors. Moreover, three major classes of endogenous opioid peptides that interact with the above opiate receptors have been recognized in the CNS: β-endorphins, enkephalins Dynorphins The opioid peptides modulate nociceptive input in two ways: block neurotransmitter release by inhibiting Ca2+ influx into the presynaptic terminal, or open potassium channels, which hyperpolarizes neurons and inhibits spike activity. They act on various receptors in the brain and spinal cord. Enkephalins are considered the putative ligands for the δ receptors, β endorphins for the μ-receptors, and dynorphins for the κ receptors. The various types of opioid receptors are distributed differently within the central and peripheral nervous system.

What is phantom pain?

Phantom or illusory pain is the experience of pain without any signals from nociceptors. It occurs in a subject with previous injuries such as amputation in which the dorsal roots are literally absent from the cord. Even though no sensory signals can enter the cord, the subject often feels extreme pain in the denervated parts of the body. For example, an amputee will often apparently feel pain in a part of his body that has been removed. The phenomenon of phantom limb pain is a common experience after a limb has been amputated or its sensory roots have been destroyed in which the pain is felt in a part of the body that no longer exists. Pain from an amputated arm is referred to the viscera as a result of disruption to the "balance" between different peripheral inputs to the dorsal horn. The source of phantom pain is complex and not well understood. It has been suggested that there may be abnormal discharges 1) from the remaining cut ends of nerves which grow into nodules called neuromas, 2) from overactive spinal neurons, 3) from abnormal flow of signals through the somatosensory cortex, or 4) from burst-firing neurons in the thalamus.

What is thalamic pain?

Stroke or occlusion in the thalamogeniculate artery (a branch of the posterior cerebral artery), which supplies the lateroposterior half of the thalamus, can result in a thalamic lesion, which is often accompanied by neurologic conditions several months after the initial event. The condition is associated with a devastating intracranial pain and sensory loss. In some cases, severe facial pain is experienced without any sensory loss. The pain resulting from an intracranial lesion is also termed "central pain." Lesions in the spinothalamic tract and its targets of termination as well as local manifestations of diencephalic lesions are usually complex. They can induce alteration of sensory, motor and endocrine components because of the functional diversity of the thalamus. Subjects with this syndrome experience spontaneous aching and burning pain in body regions where sensory stimuli normally do not lead to pain. Because the brain and the spinal cord do not contain nociceptors, the pathological process presumably directly stimulates nociceptive pathways, or it prevents the activation of the pain suppression pathways. This condition is known also as thalamic pain syndrome or Dejerive-Roussy syndrome.

What is the role of the trigeminal ganglion in the pain pathway?

The first-order nociceptive neurons from the head, face and intraoral structures have somata in the trigeminal ganglion. Trigeminal fibers enter the pons, descend to the medulla and make synaptic connections in the spinal trigeminal nucleus, cross the midline and ascend as trigeminothalamic tract (or trigeminal lemniscus). The A delta fibers terminate in the ventroposteromedial (VPM) thalamus, and the C fibers terminate in the parafasciculus (PF) and centromedian (CM) thalamus (PF-CM complex). The PF-CM complex is located within the intralaminar thalamus and are known also as intralaminar (IL) nuclei. All of the neospinothalamic fibers terminating in VPL and VPM are somatotopically oriented and from there send axons that synapse on the primary somatosensory cortex . This pathway is responsible for the immediate awareness of a painful sensation and for awareness of the exact location of the painful stimulus.

What is the neospiinothalamic tract?

The neospinothalamic tract has few synapses and constitutes the classical lateral spinothalamic tract (LST). The first-order nociceptive neurons (in the dorsal root ganglia) make synaptic connections in Rexed layer I neurons (marginal zone). Axons from layer I neurons decussate in the anterior white commissure, at approximately the same level they enter the cord, and ascend in the contralateral anterolateral quadrant. Most of the pain fibers from the lower extremity and the body below the neck terminate in the ventroposterolateral (VPL) nucleus and ventroposteroinferior (VPI) nucleus of the thalamus, which serves as a relay station that sends the signals to the primary cortex. The VPL is thought to mainly be concerned with discriminatory functions. The VPL sends axons to the primary somatosensory cortex (SCI).

What is the paleospinothalamic pathway?

The paleospinothalamic tract is phylogenetically old. The majority of the first-order nociceptive neurons make synaptic connections in Rexed layer II (substantia gelatinosa) and the second-order neurons make synaptic connections in laminae IV-VIII. The second-order neurons also receive input from mechanoreceptors and thermoreceptors. The nerve cells that furnish the paleospinothalamic tract are multireceptive or wide dynamic range nociceptors. Most of their axons cross and ascend in the spinal cord primarily in the anterior region and thus called the anterior spinal thalamic tract (AST). These fibers contain several tracts. Each of them makes a synaptic connection in different locations: 1) in the mesencephalic reticular formation (MFR) and in the periaqueductal gray (PAG), and they are also called spinoreticular tract 2) in the tectum, and these fibers are known as the spinotectal or spinomedullary tract 3) in the PF-CM complex (IL) and they are known as the spinothalamic tract. The above three fiber tracts are known also as the paleospinothalamic tract. The innervation of these three tracts is bilateral because some of the ascending fibers do not cross to the opposite side of the cord. From the PF and CM complex, these fibers synapse bilaterally in the somatosensory cortex The paleospinothalamic pathway also activates brain stem nuclei which are the origin of descending pain suppression pathway regulating noxious input at the spinal cord level

What are the visceral nociceptors?

Visceral organs contain mechanical pressure, temperature, chemical and silent nociceptors. The visceral nociceptors are scattered, with several millimeters between them, and in some organs, there are several centimeters between each nociceptor. Many of the visceral nociceptors are silent. The noxious information from visceral organs and skin are carried to the CNS in different pathways

What are nociceptors?

sensory receptors that detect signals from damaged tissue or the threat of damage and indirectly also respond to chemicals released from the damaged tissue. Nociceptors are free (bare) nerve endings found in the skin, muscle, joints, bone, and viscera. Recently it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect damage. The cell bodies of nociceptors are mainly in the dorsal root and trigeminal ganglia.