What is pain? Fredrik Hellberg 10p Extend Physiology, University of Kalmar, 2003

Transcription

1 What is pain? Fredrik Hellberg 10p Extend Physiology, University of Kalmar, 2003

2 General information The sensation that I in this work will call pain burning, aching, stinging, and soreness are the most distinctive of all the sensory modalities. Pain is a submodality of somatic sensation like pressure, touch, and position sense and serves a vital defensive function: It warns of damage that should be avoided or cared for. When children with insensitivity to pain harm themselves severely, the injury may go ignored and result in permanent damage. Unlike other somatic submodalities, and unlike vision, hearing, and smell, pain has a vital and primitive importance, responsible for the effective and emotional aspect of pain awareness. Moreover, the intensity with which pain is felt is affected by surrounding conditions, and the same stimulus can create different responses in different persons under comparable situations. Pain is a percept; it is an unlikable sensory and emotional experience connected to real or latent tissue damage. Even though pain is mediated by the nervous system, a difference between pain and the neural mechanisms of nociception the response to perceived or actual tissue damage is significant both clinically and in research. Certain tissues have specific sensory receptors, called nociceptors, which are activated by noxious insult to peripheral tissues. Nociception, does not essentially lead to the experience of pain. Hence, the association between nociception and the perception of pain provides one more example of the rule that perception is a creation of the brain s construct and enlightenment of sensory input. The greatly individual character of pain is one of the factors that make it complicated to define and to take care of clinically. There are no painful stimuli stimuli that often bring out the perception of pain in all individuals. For instance, a lot of wounded military do not sense pain until they are carefully removed from fight. In the same way, athletes seldom detect their injuries until the sport is over. Pain can be persistent or chronic. Persistent pain describes many clinical circumstances and is the main cause why patients search for medical attention whereas chronic pain appears to supply no practical function; it only makes patients unhappy. Persistent pains can be subdivided into two wide components, nociceptive and neuropathic. Nociceptive pains result from the direct activation of nociceptors in the soft tissue in response to tissue wound and usually come up from accompanying inflammation. Neuropathic pains result from direct damage to nerves in the peripheral or central nervous system and often have a burning or electric sensation. Neuropathic pains consist of the syndromes of reflex sympathetic dystrophy and postherpetic neuralgia, a cruel pain that occurs in some patients after a bout of shingles. Phantom limb pain (see page 12 for more details) can occur after shocking or surgical limb amputation. Anesthesia dolorosa, factually pain in the absence of sense, some times follows healing transaction of sensory nerves (e.g. the dorsal root nerves) performed in an effort to block chronic pain. 1

3 Noxious insult triggers nociceptors Damaging stimuli to the skin or subcutaneous tissue, such as joints or muscle, activates numerous classes of nociceptor terminals, the peripheral endings of primary sensory neurons, which cell bodies are placed in the dorsal roots ganglia and trigeminal ganglia. I consider here three major classes of nociceptors thermal, mechanical, and polymodal as well as a class termed silent nociceptors. Thermal nociceptors are activated by tremendous temperatures (> 45 C or < 5 C). They have small-diameter, thinly myelinated Aδ fibers that transfer signals at almost 5 30 m/s. Mechanical nociceptors are activated by rigorous pressure applied to the skin. They also have thinly myelinated Aδ fibers conducting at 5 30 m/s. Polymodal nociceptors are activated by high-intensity mechanical, chemical, or thermal (both hot and cold) stimuli. These nociceptors have small-diameter, nonmyelinated C fibers that conduct slowly, usually at velocities of less than 1.0 m/s. These three classes of nociceptors are generally spread in skin and deep tissues and frequently work together. For instance, when you hit your head with a sledge hammer (and hopefully not die), a spiky initial pain is felt immediately, followed later by an extra extended hurting, sometimes burning next pain. The fast spiky pain is transmitted by Aδ fibers that bear information from thermal and mechanical nociceptors. The slow dull pain is transmitted by C fibers that are activated by polymodal nociceptors. Unlike the specilialized somatosensory receptors for touch and pressure, most nociceptors are free nerve endings. The mechanism by which noxious stimuli depolarize free sensory endings and produce action potentials is not identified. The membrane of the nociceptor is thought to hold proteins that alter the thermal, mechanical, or chemical energy of noxious stimuli into a depolarizing electrical potential. One such protein is the receptor for capsaicin, the active ingredient in hot peppers. The capsaicin, or vanilloid, receptor is found exclusively in primary afferent nociceptors and mediates the pain-producing actions of capsaicin. Significantly, the receptor in addition responds to noxious heat stimuli, which suggests that it also is a transducer of painful heat stimuli. Many factors in addition to the level of action of Aδ and C fibers decide the position, power, and class of the pain. While the awareness of touch or pressure is consistent when touchpressure receptors are electrically stimulated, activation of the same nociceptors can lead to different reported sensations. This can be illustrated with a simple test in which blood pressure cuff is placed around the arm and inflated above systolic pressure for about 30 minutes. This procedure produces temporary anoxia and blocks conduction in large-diameter Aδ and Aβ fibers; C fibers are still capable of conduct action potentials and react to noxious stimulation. The obstruction of transmission occurs since these fibers have a superior metabolic requirement than C fibers and, as a result, large motor axons no longer conduct impulses and the arm is paralyzed. In addition, there is no touch, vibration, or joint sensation because transmission along Aβ sensory fibers that project into dorsal column-medial lemniscal system is blocked. In the absence of conductions by the Aδ and Aβ fibers, the perception of pain is not normal. For instance, a pin prick, a pinch, or ice cannot be distinguished from each other. Rather each of these normally distinct stimuli now produces burning pain. 2

4 This trial shows that large-diameter Aβ fibers do add normal perception of stimulus quality, even though they do not react directly to noxious stimuli. Activity in the large-diameter fiber systems not only modifies the perception of pain but also attenuates it. Thus the reflexive shaking of the hand in response to a burn effectively stimulates large-diameter afferents that can attenuate the pain. Although the perception of pain normally varies among individuals and in different contexts, abnormal pain states can be diagnosed reliably. In pathological situations activation of nociceptors can lead to two types of abnormal pain states: allodynia and hyperalgesia. In allodynia, pain results from stimuli that normally are innocuous: a light stroking of sunburned skin, the movement of joints in patients with rheumatoid arthritis, even getting out of bed the morning after a vigorous workout (particularly when one is not in shape). Patients with allodynia do not sense constant pain; in lack of a stimulus there is no pain. In contrast, patients with hyperalgesia, an extreme response to noxious stimuli, often perceive pain impulsively. Nociceptive afferent fibers terminate on neurons in the dorsal horn of the spinal chord Nociceptive afferent fibers end predominantly in the dorsal horn of the spinal chord. The dorsal horn can be subdivided into six separate layers (laminae) on the basis of the cytological features of its resident neurons. Classes of primary afferent neurons that convey distinct modalities end in separate laminae of the dorsal horn. Thus there is a close correspondence between the functional and anatomical organization of neurons in the dorsal horn of the spinal chord. Nociceptive neurons are located in the superficial dorsal horn, in the marginal layer (also called lamina I) and the substantia gelatinosa (lamina II). The greater part of these neurons get direct synaptic input from Aδ and C fibers. A lot of of the neurons in the marginal layer (lamina I) react exclusively to noxious stimulation (and thus are called nociceptive-specific neurons) and project to higher brain centers. Some neurons in this layer, called wide-dynamicrange neurons, respond in a graded fashion to both nonnoxious and noxious mechanical stimulation. The substantia gelatinosa (lamina II) is made up almost exclusively of interneurons (both excitatory and inhibitory), some of which respond only to nociceptive inputs while others respond also to nonnoxious stimuli. Laminae III and IV are situated ventral to the substantia gelatinosa and hold neurons that acquires monosynaptic input from Aβ fibers. These neurons act in response to nonnoxious stimuli and have moderately restricted receptive fields that are ordered topographically. Lamina V contains primarily wide-dynamic-range neurons that project to the brain steam and to regions of the thalamus. These neurons receive monosynaptic input from Aβ and Aδ fibers. They also receive input from C fibers, either directly on their dendrites, which lengthen dorsally into the superficial dorsal horn, or indirectly via excitatory interneurons that themselves receive input directly from C fibers. Many neurons in lamina V also receive nociceptive input from visceral structures. The junction of somatic and visceral nociceptive input to lamina V neurons may explain referred pain, a condition in which pain from injury to a visceral structure is predictably displaced to other areas of the body surface. For example, patients with myocardial infraction frequently report pain not only from the chest but also from the left arm. 3

5 One clarification for this single projection neuron receives input from both regions. As a result, higher centers cannot distinguish the cause of the input and incorrectly attribute the pain to the skin maybe because the cutaneous input predominates normally. An alternative basis for referred pain is the branching of the axons of peripheral sensory neurons, but this is likely to contribute only to a marginal of cases because single afferent fibers hardly ever innervate both a visceral and remote cutaneous location. Neurons in lamina VI receive inputs from large-diameter afferents from muscles and joints and respond to nonnoxious manipulation of joints. These neurons are believed not to donate to the transmission of nociceptive communication. Finally, neurons in ventral horn laminae VII and VIII, many of which respond to noxious stimuli, have more intricate response properties because the nociceptive inputs to lamina VII neurons are polysynaptic. In addition, although most dorsal horn neurons receive input from only one side of the body, many neurons in lamina VII respond to stimulation of either side. Thus, neurons of lamina VII, though their connections with the brain steam reticular formation, may contribute to the diffuse nature of many pain conditions. Nociceptive afferent fibers use glutamate and neuropeptides as neurotransmitters Synaptic contact between nociceptors and dorsal horn neurons is mediated by chemical neurotransmitters released from central sensory nerve endings. The main excitatory neurotransmitter released by Aδ and C fibers as well as by nonnociceptive afferents is the amino acid glutamate. The release of glutamate from sensory terminals evokes fast synaptic potentials in dorsal horn neurons by activating the AMPA-type glutamate receptors. The primary afferent fibers of nociceptive neurons also elicit slow excitatory postsynaptic potentials in dorsal horn neurons by releasing peptide transmitters. Small-diameter primary afferent terminals in the dorsal horn contain both small electron-translucent synaptic vesicles that store glutamate and large dense-core vesicles that store neuropeptides. Of the many neuropeptides present in nociceptive sensory neurons, substance P has been studied in most detail. Substance P is released from C fibers in response to tissue injury or to intense stimulation of peripheral nerves. Glutamate and neuropeptides are released in concert from primary afferent terminals and have distinct physiological actions on postsynaptic neurons, but they act coordinately to control the firing properties of postsynaptic neurons. Neuropeptides, including substance P, seem to improve and prolong the actions of glutamate. The variety of action of the two classes of transmitters may also vary. The actions of glutamate released from sensory terminals are confined to postsynaptic neurons in the direct area of the synaptic terminal as a consequence of the efficient reuptake of amino acids into glial cells or nerve terminals. In contrast, neuropeptides released from sensory terminals can diffuse considerable distance from their site of release because there is not a specific mechanism. Therefore, the release of neuropeptides from a single afferent fiber is likely to manipulate many postsynaptic dorsal horn neurons. This feature, together with the fact that peptide levels are significantly increased in persistent pain conditions, suggest that peptide action contribute both to the excitability of dorsal horn neurons and to the unlocalized character of many pain conditions. 4

6 Hyperalgesia has both peripheral and central origins Changes in nociceptor sensitivity underlie primary hyperalgesia Upon the continual application of noxious mechanical stimuli, close by nociceptors that were previously insensitive to mechanical stimuli now become sensitive, a phenomenon called sensitization. This mechanism is believed to be mediated by an axon reflex, similar to the spread of vasodilation in the neighborhood of a localized region of cutaneous injury. The sensitization of nociceptors after damage or inflammation results from the release of variety of chemicals by the busted cells and tissues in the neighborhood of the damage. These substances include histamine, bradykinin, leukotrienes, acetylcholine (ACh), serotonin, prostaglandins, and substance P. Each originates from a different population of cells, but all act to diminish the threshold for activation of nociceptors. A few, however, also activate nociceptors. For instance, histamine released from a damage mast cell in response to tissue injury activates polymodal nociceptor. ATP, ACh, and serotonin are released from damaged endothelial cells and platelets and act alone or in combination to sensitized nociceptors via other chemical agents, such as prostaglandins and bradykinin. Prostaglandin E 2 is a metabolite of arachidonic acid and is produced by the enzyme cyclooxygenase released by damage cells. Aspirin and other nonsteroidal anti-inflammatory analgesics are effective in controlling pain because they block the enzyme cyclooxygenase, thereby preventing the synthesis of prostaglandins. The peptide bradykinin is one of the most active pain-producing agents. This high amount of activity is believed to result from its two distinct actions. First, bradykinin activates both Aδ and C nociceptors directly; second, it increases the synthesis and release of prostaglandins from nearby cells. Primary nociceptive neurons control their chemical environment through chemical mediators, which are synthesized in the cell body and then transported to the peripheral terminal, where they are stored and released upon depolarization of the terminal. For instance, injury leads to the release of two neuroactive peptides substance P and calcitonin gene-related peptide from nociceptive sensory endings. These two peptides add to the spread of edema by acting directly on venules to produce vasodilation. They also contribute to hyperalgesia by leading to the release of histamine from mast cell, which decreases the threshold for activation of nociceptors. The cardinal signs of inflammation are heat (calor), redness (rubor), and swelling (tumor). Local application of substance P can replicate all three of these symptoms. Heat and redness are produced by dilation of peripheral blood vessels, whereas swelling results from plasma extravasasion, a course of action in which proteins and cells leak out of postcapillary venules accompanied by fluid. Since this inflammation is mediated by neural activity, it is referred to as neurogenic inflammation. Nonpeptide antagonists of substance P can completely block neurogenic inflammation in humans, an example of how the understanding of basic mechanisms of nociception can have clinical applications. 5

7 The hyperexcitability of dorsal horn neurons triggers centrally mediated hyperalgesia Under states of cruel and persistent injury, C fibers fire repetitively and the response of dorsal horn neurons increases progressively. This phenomenon, called wind-up, is dependent on the discharge of the excitatory transmitter glutamate from C fibers and subsequent opening of postsynaptic ion channels gated by the N-methyl-D-aspartate (NMDA)-type glutamate receptor. Thus, blocking NMDA-type receptor activity can block wind-up. Noxious stimulation can consequently produce long-term changes in dorsal horn neurons in a style similar to long-term potentiation, a process by which long-term changes in synaptic transmission are elicited in the hippocampus and other regions of the brain. NMDA-type glutamate receptors also have a role in producing the hyperexcitability of dorsal horn neurons that follows tissue injury. This phenomenon is termed central sensitization, to distinguish it from the sensitization that occurs at the peripheral ending of sensory neurons via activation of the arachidonic acid cascade. These long-term changes in the excitability of dorsal horn neurons constitute a memory of the C fiber input. In response to peripheral noxious stimuli, neurons in the dorsal horn show an initiation of immediate early genes that encode transcription factors such as c-fos. There is also an upregulation in the expression of neuropeptides and neurotransmitters and their receptors that presumably changes the physiological properties of these neurons. Alterations in the biochemical properties and excitability of dorsal horn neurons can lead to impulsive pain and can reduce the threshold for the creation of pain. This is apparent in the dramatic experience of phantom limb pain, the persistent sensation of pain that appears to originate from the region of an amputated limb. Until recently, limb amputation was performed under general anesthesia in order to eliminate awareness and memory of the procedure. The spinal cord, however, still experience the insult of the surgical procedure because central sensitization still occurs under general anesthesia. To stop central sensitization, therefore, general anesthesia is now supplemented with straight spinal administration of an anesthetic agent or local access of anesthetics at the injury site. Nociceptive information is passed over from the spinal cord to the thalamus and cerebral cortex along five ascending pathways Information about tissue injury is carried from spinal cord to the brain through five major ascending pathways: the spinothalamic, spinoreticular, spinomesencephalic, cervicothalamic, and spinohypothalamic tracts. The spinothalamic tract is the most vital ascending nociceptive pathway in the spinal cord. It comprises the axons of nociceptive-specific and wide-dynamic-range neurons in laminae V- VII of the dorsal horn. These axons project to the contralateral side of the spinal cord and ascend in the anterolateral white matter, terminating in the thalamus. Electrical stimulation of the spinothalamic tract fallout in pain whereas lesions of the tract (achieved by a procedure called anterolateral cordotomy) result in marked reductions in pain sensation on the side opposite the spinal chord lesion. 6

8 The spinoreticular tract comprises the axons of neurons in laminae VII and VIII. It ascends in the anterolateral quadrant of the spinal cord and terminates in both the reticular formation and thalamus. In difference to the spinothalamic tract, many of the axons of the spinoreticular tract do not cross the midline. The spinomesencephalic tract comprises the axons of neurons in laminae I and V. It projects in the anterolateral quadrant of the spinal cord to the mesencephalic reticular structure and periaqueductal gray matter, and via the spinaparaprachial tract, it projects to the parabrachial nuclei. In turn, neurons of the parabrachial nuclei project to the amygdale, a main component of the limbic system, the neural system implicated in emotion. Thus the spinomesencephalic tact is thought to contribute to the affective component of pain. Many axons of this pathway project in the dorsal part of the lateral funiculus rather than in the anterolateral quadrant. Thus, if these fibers are spread in surgical procedures designed to relieve the pain, such as anterolateral cordotomy, pain may persist or recur. The cervicothalamic tract occurs from neurons in the lateral cervical nucleus, situated in the lateral white matter of the upper two cervical segments of the spinal cord. The lateral cervical nucleus receives input from nociceptive neurons in laminae III and IV. Most axons in the cervicothalamic cross the midline and ascend in the medial laminiscus of the brain stem to nuclei in the midbrain and to the thalamus. Some axons from laminae III and IV project through the dorsal columns of the spinal cord (together with the axons of large-diameter myelinated primary afferent fibers) and terminate in the cuneate and gracile nuclei of the medulla. The spinohypothalamic tract comprises the axons of neurons in laminae I, V, and VIII. It projects directly to supraspinal autonomic control centers and is thought to activate intricate neuroendocrine and cardiovascular reactions. Thalamic nuclei spread afferent information to the cerebral cortex Some nuclei in the thalamus process nociceptive information. Two are particularly important: the lateral and medial nuclear groups. The lateral nuclear cluster of the thalamus comprises the ventroposterior medial nucleus, the ventroposterior lateral nucleus, and the posterior nucleus. These nuclei receive input via the spinothalamic tract, primarily from nociceptivespecific and wide-dynamic-range neurons in laminae I and V of the dorsal horn of the spinal cord. Neurons in these nuclei have small receptive fields, as do to the spinal neurons that project to them. The lateral thalamus may therefore be mostly concerned with mediating information about the location of an injury, information usually conveyed to consciousness as acute pain. Injury to the spinothalamic tract and its targets causes a severe pain termed central pain. For instance, an infarct in a small region of the ventroposterolateral thalamus can produce thalamic (Dejerine-Roussy) syndrome. Patients with this syndrome often experience a spontaneous very strong pain and other abnormal sensations (dysesthesia) in regions of the body where noxious stimuli normally do not lead to pain. In addition, in certain chronic pain conditions, electrical stimulation of the thalamus results in intense pain. In one striking case sensations of angina pectoris were rekindled in a patient by electrical stimulation of the thalamus. The report of the patient was so realistic that the anesthesiologist thought the patient was having a heart attack. 7

9 These observations highlights that there is a change in thalamic and cortical circuits in chronic pain conditions. Thus, patients who have experienced persistent pain due to injury have functionally different brains from those who have not experienced such pain. The medial nuclear cluster of the thalamus comprises the central lateral nucleus of the thalamus and the intra-laminar complex. Its main input is from neurons in laminae VII and VIII of the dorsal horn. The pathway to the medial thalamus is the first spinothalamic projection to appear in the development of mammals and is therefore known as the paleospinothalamic tract. This pathway is also often referred to as the spinoreticulothalamic tract because it includes polysynaptic inputs via the reticular formation of the brain stem. The projection from the lateral thalamus to the ventroposterior lateral and medial nuclei is most developed in primates and is therefore known also as the neospinothalamic tract. A lot of neurons in the medial thalamus respond optimally to noxious stimuli but also have extensive projections to the basal ganglia and many different cortical areas. They are therefore concerned not only with stimuli that activate a nonspecific arousal system. The cerebral cortex contributes to the processing of pain Until lately most study on the central processing of pain has concerned on the thalamus. But, pain is an intricate perception that is influenced by former experience and by the context within which the noxious stimulus occurs. Neurons in several regions of the cerebral cortex respond selectively to nociceptive input. Some of these neurons are located in the somatosensory cortex and have small receptive fields. Thus, they may not supply to the diffuse aches that characterize most clinical pain. Position emission thomography (PET) imaging studies of humans also indicate that two other regions of cortex, the cingulate gyrus and the insular cortex, are involved in the response to nociception. The cingulate gyrus is part of the limbic system and is thought to be concerned with processing the emotional part of pain. The insular cortex receives direct projections from the medial thalamic nuclei and from the ventral and posterior medial thalamic nucleus. The neurons in the insular cortex process information on the internal condition of the body, contributing to the autonomic component of the overall pain response. Indeed, lesions of the insular cortex result in an unusual syndrome called asymbolia for pain. Patients with this condition perceive noxious stimuli as painful and can distinguish sharp from dull pain but do not display appropriate emotional responses to the pain. The insular cortex may therefore integrate the sensory, affective, and cognitive components, all of which are necessary for normal responses. Pain can be directed by central mechanisms One of the most extraordinary discoveries in pain research is that the brain has modulatory tracks whose key function is to control the perception of pain. Several modulatory systems in the central nervous system affect responses to noxious stimuli. The initial site of modulation is in the spinal cord, where interconnections between nociceptive and nonnociceptive afferent pathways can control the transmission of nociceptive information to higher centers in the brain. 8

10 The equilibrium of activity in nociceptive and nonnociceptive primary afferent fibers can modulate pain: the gate control theory Pain is not only a direct creation of the activity of nociceptive afferent fibers but is synchronized by action in other myelinated afferents that are not directly concerned with the transmission of nociceptive information. The idea that pain results form the balance of activity in nociceptive and nonnociceptive afferents was formulated in the 1960s and was called the gate control theory. This theory incorporates several key observations. First, neurons of lamina V, and possibly lamina I, receive convergent excitatory input from both nonnociceptive Aβ fibers and nociceptive Aδ and C fibers. Second, the large-diameter Aβ fibers inhibit the firing of neurons in lamina V by activating inhibitory interneurons in lamina II. Third, the Aδ and C fibers excite inhibitory interneurons in lamina II, which are activated by the Aβ fibers. Simply put, nonnociceptive afferents close and nociceptive afferents open a gate to the central transmission of noxious input. The gate control theory also offers a neurophysiologic foundation for the observation that a vibratory stimulus that selectively activates large-diameter afferents can reduce pain. The gate control theory is the rationale for the use of transcutaneous electrical stimulation (TENS) and dorsal horn column stimulation for the release of pain. In TENS, electrodes are used to activate large-diameter afferent fibers that overlap the area of injury and pain. Stimulation of the dorsal column via surface electrodes presumably relieves pain because it activates large numbers of Aβ fibers synchronously. This mechanism of analgesia is topographically precise. The area of the body in which pain is synchronized is linked anatomically to the segments of the spinal cord where the nociceptive and nonnociceptive afferents terminate. One does not shake the left leg to relieve pain in the right arm. Direct electrical stimulation of the brain produces analgesia A powerful counterbalance to nociception has been found in experimental animals. Here stimulation of the periaqueductal gray region, the gray matter that surrounds the third ventricle and the cerebral aqueduct, produces a deep and discriminating analgesia. This stimulation-produced analgesia is remarkably specific. It is not, for example, associated with a generalized inhibition of afferent inputs. The animal still responds to touch, pressure, and temperature within the body area that is analgesic it simply feels less pain. Stimulation of the periaqueductal gray matter also blacks spinally mediated withdrawal reflexes that are normally evoked by noxious stimulation. Blockade occurs because stimulation recruits downward pathways that hinder nociceptive neurons in the spinal cord. It also hinders the firing of nociceptive neurons in laminae I and V. Stimulation-produced analgesia has proved to be an effective way of relieving pain in humans under various conditions. Few neurons in the periaqueductal gray matter project directly to the dorsal horn of the spinal cord. Instead they make excitatory associations with neurons of the rostroventral medulla, in particular with serotonergic neurons in the midline of the nucleus raphe magnus. 9

11 Neurons of this nucleus project to the spinal cord via the dorsal part of the lateral funiculus and make inhibitory associations with neurons in laminae I, II, and V of the dorsal horn. Stimulation of the rostroventral medulla inhibits dorsal horn neurons, together with neurons of the spinothalamic tract that respond to noxious stimulation. Other downward inhibitory systems that hold back the action of nociceptive neurons in the dorsal horn begin in the noradrenergic locus ceruleus and other nuclei of medulla and pons. These descending projections block the output of neurons in laminae I and V by direct and indirect inhibitory actions. They also interact with endogenous opioid-containing circuits in dorsal horn. Opiate-induced analgesia involves the same pathway as stimulation-produced analgesia Even since the discovery of the opium poppy, it has been recognized that opiates such as morphine and codeine are useful analgesic agents. Are the neural circuits involved in stimulation-produced analgesia and opiate-induced analgesia related? Microinjection of small quantities of morphine or other opiates straight into specific regions of the rat brain produces a dominant analgesia by inhibiting the firing of nociceptive neurons in the dorsal horn. The periaqueductal gray region is among the most sensitive sites for eliciting such analgesia. Morphine-induced analgesia is blocked by injection of the opiate antagonist naloxone into either the periaqueductal gray region of the serotonergic nucleus raphe magnus. Moreover, bilateral transection of the dorsal lateral funiculus in the spinal cord blocks both stimulation-produced and morphine-induced analgesia. These observations indicate that morphine also produces analgesia by activating descending inhibitory pathways. Opioid peptides contribute to the endogenous pain control system Endogenous opioid peptides and their receptors are situated at key positions in the pain modulatory structure The opiate antagonist naloxone blocks stimulation-produced analgesia just like morphineinduced analgesia. This finding recommended that the brain contains specific receptors for opiates. Three main classes of opioid receptors have been identified: µ, δ and κ. The genes coding each of these receptors have been cloned and found to be members of the G proteincoupled class of receptors. These receptors were originally defined on the foundation of their affinity for binding agonists. Opiate alkaloids, such as morphine, are potent agonists at the µ receptor. Indeed, at the µ receptor there is a high relationship between the potency of an analgesic and it affinity for binding to the receptor. Consistent with this idea, mice in which the gene for the µ opioid receptor has been deleted exhibit insensitivity to morphine and other µ receptor agonists. Naloxone also binds the µ receptor, but antagonizes the act of morphine by displacing it from the receptor without itself activating the receptor. The µ-opioid receptor are highly concentrated in periaqueductal gray matter, the ventral medulla, and the superficial dorsal horn of the spinal cord, all of which are important in the regulation of pain. 10

12 However, they are found at many other sites in the central and peripheral nervous systems along with the other opioid receptors. The frequent distribution of these receptors explains the finding that systematically administrated morphine affects many other physiological processes. The discovery of endogenous receptors for opiates in the brain raised the issue of whether there was matching endogenous ligands for these receptors. Three main classes of endogenous opioid peptides that interact with the opioid receptors have now been identified: enkephalins, β-endorphin, and dynorphins. These three opioid peptides are generated from large polyprotein precursors encoded by three distinct genes: the proenkephalin gene, the proopiomelanocortin gene, and the prodynorphin genes. The two enkephalins leucine and methionine enkephalin are both small pentapeptides. β- Endorphin is a result of proopiomelanocortin (POMC), a precursor polypeptide that is produced primarily in the pituitary and also gives rise to adrenocorticotropic hormone (ACTH). Both β-endorphin and ACTH are released into the bloodstream in response to stress. Dynorphins are derived from the polyprotein product of the dynorphin gene. Despite difference in the length of these endogenous opioid peptides, each contains a shared tetrapeptide sequence Tyr-Gly-Gly-Phe. Enkephalins are active at both µ and δ receptors and dynorphin is a relatively selective agonist of the κ receptor. The peptides programmed by the three opioid genes are distributed differently in the central nervous system, but members of each family are located at sites connected with the processing or modulation of nociception. Neuronal cell bodies and axon terminals containing enkephalin and dynorphin are found in the periaqueductal gray matter, the rostral ventral medulla, and the horn of the spinal cord, in particular in laminae I and II. β-endorphin is confined primarily to neurons in the hypothalamus that send projections to the periaqueductal gray region and to noradrenergic nuclei in the brain stem. In addition to the three classical opioid receptors (the µ, δ, and κ receptors), a novel opioidlike orphan receptor has also been identified. The orphan receptor s endogenous ligand is a 17-amino-acid peptide called orphanin FQ or nociceptin (OFQ/N1-17), which resembles dynorphin. The OFQ/N1-17 receptor is expressed widely in the nervous system, and the peptide appears to participate in the regulation of nociception and the broad range of other physiological and behavioral functions. Activation of opioid receptors by morphine controls pain Opioid receptors are located in regions of the nervous system other than those that mediate pain and thus many of the side effects of using opioids as narcotics can be understood in terms of the distribution of these receptors. For example, receptors are present in the muscles of the bowel and the anal sphincter and account for constipation, a common side effect of the action of opiates. Receptors in the cells of the nucleus of the solitary tract in the brain stem account for respiratory depression and cardiovascular changes. To minimize the side effects of systemic injection, morphine is now also administrated locally into the spinal cord. The dorsal horn has a high concentration of opioid receptors, and morphine administration inhibits the firing of dorsal horn neurons responsive nociceptive stimuli. Indeed, intrathecal or epidular injection of morphine into the cerebrospinal fluid of the spinal cord subarachnoid space produces a profound and prolonged analgesia. 11

13 These routes of administration are now commonly used in the treatment of postoperative pain, such as the pain that sometimes follows a Caesarean section. In addition to its prolonged effect, the analgesia achieved by intrathecal opiates is associated with minimal side effects because the drug does not diffuse far from the site of injection. Continuous infusion of morphine to the spinal cord has also been used for the treatment of cancer pain. How does spinal administration of morphine produce its profound analgesic effects? Morphine acts by mimicking the action of the endogenous opioids in this region. The superficial dorsal horn contains a high density of interneurons containing enkephalin and dynorphin, and the terminals of these cells lie close to the synapses between nociceptive afferents and projection neurons. Opioid receptors of all three classes are located on the terminals of the nociceptive afferents and on the dendrites of postsynaptic dorsal horn neurons. Opiates such as morphine and opioid peptides regulate nociceptive transmission with two inhibitory actions: a postsynaptic inhibition, produced partly by increasing K + conductance, and presynaptic inhibition of the release of glutamate, substance P, and other transmitters from the terminals of sensory neurons. The opioid-caused decrease in transmitter release from primary afferents results either indirectly from decrease in Ca 2+ entry into the sensory terminals (as a result of increased K + conductance) or directly from a decrease in Ca 2+ conductance. Opioid receptors are not confined to the central terminal of primary afferent fibers but are also located on the peripheral terminals in skin, joints, and muscle. For example, after arthroscopic surgery, prolonged relief of pain result from local injection of morphine into the treated joint at doses that are ineffective when administrated systemically. Peripheral administration can significantly reduce side effects. The source of the endogenous opioids that normally activate opioid receptors on peripheral sensory endings is unclear. Two possibilities are the chromaffin cells of the adrenal medulla and various immune cells that migrate to injury sites as part of the inflammatory process and there synthesize endogenous opioids. Phantom limb pain The presence of a phantom limb is now seen as a neural consequence of amputation. This has not constantly been the case. Throughout history, phantom limbs have fascinated researchers and driven numerous investigations in an effort to describe phantom phenomena and to understand why they occur. The existence of a phantom limb is seldom distressing for an amputee, mainly when they are informed about its likely presence prior to amputation. In fact, many amputees welcome a phantom limb as it allows them to use prosthesis naturally. Though, in addition to phantom feeling, a grate many amputees suffer from phantom limb pain. Phantom limb pain is defined as painful sensations referred to the absent limb. The phantom phenomena Pain in the residual limb is defined as pain at the site of an extremity amputation. Pain in the residual limb, not surprisingly, is particularly common in the early post-amputation phase. Pain in the residual limb can persist beyond the stage of post-surgery healing. Immediate postsurgical pain is described as a stabbing, shocking or burning, and occurs in the lower end of the stump, close to the scar. 12

14 But, in contrast to immediate post-surgical pain, pain in the residual limb continues for many years after the surgical cut has healed and can take place in the lack of stimulation, or otherwise, in response to light stimulation of the stump. Phantom sensation is defined as any sensation of the absent limb except pain and is experienced by virtually everyone who undergoes limb amputation. Once a body part has been excised, either by trauma or surgery, the feeling persists that the body part is still present. In addition, phantom limb sensation is reported in the absence of amputation, for example, in patients with sensory loss due to spinal cord injury where normal sensation is absent. Moreover, phantom limbs have been induced in experimental situations using an anesthetic block of an intact limb. Localization Immediately following amputation, the phantom limb resembles the pre-amputation limb in shape, extent, and volume. In addition, it is reported to move in space and time in much the same way as the pre-amputation limb did. The reality of a phantom limb is such that a lot of amputees report trying to use the limb. Despite the reality of the phantom limb, it does not remain a compete reproduction of the pre-amputation limb. Over time, the proximal part of the phantom often fades. The remaining phantom is comprised of the distal of the limb, usually those parts that have the greatest representation in the somatosensory cortex. For example, in those with an upper limb amputation, the thumb is experienced more vividly than the remaining fingers and the balls of the fingers have greater clarity than the remaining part of the hand. It has been proposed that changes in the receptive fields of the dorsal horn neurons account for some aspects of phantom sensation. Expended receptive fields of neurons in the spinal cord have been observed in a number of animal studies. More evidence of cortical reorganization followed amputation comes from experimental studies of monkeys. In a microelectrode study, the area of somatosensory cortex previously occupied by a digit was to be taken over by cutaneous input from the stump and surrounding tissue following amputation. Cells identified in the area of sensory cortex which originally had receptive fields that included the amputated digit responded, after amputation, to input of the adjacent digits, the palm of the hand, and the amputation stump. Phantom pain About 60-80% of amputees experience phantom limb pain, but several studies report that severe phantom limb pain occurs in only 0.5 to 5% of all amputees. Localization Like phantom sensation, which predominates in distal portion of the phantom over time, phantom limb pain is also primarily localized to the distal part of the missing limb. In upper limb amputees, phantom pain is normally felt in the fingers; palm of the hand, and occasionally the wrist and in lower limb amputees, phantom pain is generally experienced in the toes, ball of the foot, instep, top of the foot and ankle. Given the similarity in localization, it is possible that the change in receptive fields and cortical reorganization observed following limb amputation are related to both phantom limb pain and phantom sensation. 13

15 Duration Many studies suggest that phantom limb pain either diminishes or fades away during the first 2 years post-amputation, Quality Two of the most widespread descriptions applied to phantom limb pain are flaming and cramping. Other terms are also used. Phantom limb pain has been described as numb, smarting, stinging, throbbing, piercing, and tearing. Fundamental explanations for phantom limb pain Physiological mechanisms A number of physiological mechanisms have been offered to explain the development of phantom phenomena. Recent research has highlighted the function of peripheral nerve fibers in the explanation of phantom limb pain. Following amputation, fibers from the cut end of nerves grow into nodules (neuromas) which generate abnormal impulses. These impulses activate central nervous system neurons and may result in the perception of phantom pain. This hypothesis receive support from tests if stumps, which frequently revel pathological findings (skin pathology, circulatory disturbance, infection, bone spurs, or neuromas). Phantom pain is reported more frequently by patients with observable stump pathology and co-occurs in terms of frequency and intensity with pain in the residual limb. Moreover, surgical removal of neuromas sometime provides relief from phantom limb pain. Mechanical, chemical, and electrical irritants applied to the nerve ending in the stump have been shown to intensify phantom limb pain, and local anesthesia has been shown to eliminate phantom limb pain. Although these studies show that peripheral factors undoubtedly play a role in phantom limp pain, there is proof to suggest that they are not the primary eliciting factor. Pain can also occur in the absence of stump pathology and surgical revision of the stump, as well as removal of neuromas, has only limited success in alleviating phantom pain. Phantom pain can occur in the absence of nerve damage, such as when information from the periphery is blocked, such as when there has been a complete transection of the spinal cord. Livingston proposed that phantom limb pain can be attributed to abnormal firing patterns in the internuncial neurons in the spinal cord. Carlen and his colleagues proposed that peripheral and spinal factor alone accounted for phantom limb pain. These researches argue that if higher central mechanisms, released from the inhibition of peripheral input, were critical to the experience of phantom limb pain, it would follow that phantoms experienced by paraplegics should be more vivid as they have lost more input than amputees. 14

16 Blocking NMDA receptors in the hippocampal dentate gyrus with AP5 produces analgesia in the formalin pain test A considerable body of data indicates that the hippocampus processes pain-related information, that some hippocampal neurons respond entirely to painful stimulation, and that long-term anatomical changes occur in dentate gyrus neurons, following noxious physical stimulation. NMDA receptor antagonist drugs administrated to the hippocampus interfere with long-term potentiation, learning, and memory; these same drugs, when applied to the spinal cord, prevent the long-term neurophysiological changes caused by noxious physical stimulation. This experiment tested whether blocking of NMDA receptors in the hippocampal structure decreases nociceptive behaviors in an animal model of persistent human pain. The competitive NMDA receptor antagonist AP5 was injected to dentate gyrus of alert, unrestrained rats either 5 min before or 15 min following the administration of a subcutaneous injection of formalin irritant. Pain behaviors in both acute and tonic phases of the formalin test were considerably reduced by AP5 treatments. These results support the hypothesis that the hippocampal formation is involved in pain-related neural processing ant that NMDA receptor-sensitive mechanisms in the hippocampus are involved in pain perception and/or the expression of pain-related behaviors. Glutamate receptors and persistent pain: targeting forebrain NR2B subunits Tissue injury often leads to pain that lasts for an extended period of time after the wound (persistent pain). Hyperalgesia and allodynia are associated with persistent pain. In hyperalgesia, the response to noxious stimuli and the intensity of pain are increased. Allodynia is a pathological state in which the nociceptive threshold id decreased and a normally nonnoxious stimulus can induce pain. Both peripheral and central sensitization contributes to persistent pain (e.g. the sensitivity to subsequent stimuli is enhanced). Peripheral sensitization reflects amplified sensitivity of primary afferent nociceptors, and includes lowered thresholds and an increased responsiveness of the skin. In addition, both during and after injury, synaptic transmission in the central nervous system undergoes longlasting changes. Some of these central changes are permanent, altering the brain s perception of future sensory stimuli. Regardless of recent progress in dissecting the pathophysiological mechanisms of persistent pain, cellular and molecular mechanisms for the induction and maintenance of chronic pain remain unclear. An understanding of molecular and cellular mechanisms of pain transmission and modulation is essential to the development of clinical strategies aimed at alleviating chroming pain. Spinal dorsal horn: a primary site for controlling persistent pain Glutamate and substance P as sensory transmitters Neurons in the spinal cord dorsal horn and associated areas receive sensory inputs, including noxious stimuli, and convey them to supraspinal structures. The classification of molecules that are selectively involved in pain transmission is the major research focus and holds hope for the treatment of pain, as well as persistent pain. 15

17 Studies using pharmacological and behavioral approaches showed that glutamate and neuropeptides together with substance P are probable transmitters for pain. Electrophysiological investigation of sensory synaptic responses between primary afferent fibers and dorsal horn neurons provide evidence that glutamate is the principal fast excitatory transmitter, and synaptic response are mediated by postsynaptic glutamate receptors. Although α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors mediate the major component of postsynaptic current, kainate receptors preferentially contributes to synaptic responses induced by higher (noxious) stimulation intensities. Consistent with this, antagonism of both kainate and AMPA receptors yields grater analgesic effects in adult animals than AMPA receptor antagonism alone. These findings suggest that sensory modulation could be coded in part by different postsynaptic neurotransmitter receptors. Not all sensory synapses are useful or effective in normal conditions. In young animals, silent glutamatergic synapses, or synapses containing only NMDA receptor-mediated responses, were found between sensory afferent fibers and dorsal horn neurons. Conversion of such silent synapses to a functional, or activated, state contributes to enhancement of synaptic responses by serotonin, an important transmitter of descending projecting pathways. Furthermore, pure NMDA receptors were also reported in spinal dorsal horn of adult animals. These synapses are functional because of possible distal dendrite locations or insensitivity to magnesium blockade. In addition to glutamate, several neuropeptides, including substance P, are considered to act as sensory transmitters. Resent studies using whole-cell patch-clamp recordings reveal rather rapid substance P and neurokinin A-mediated synaptic current in synapses between primary afferent fibers and dorsal horn neurons. NMDA receptors as a synaptic enhancer What makes glutamatergic synapses mostly unique is that they can undergo long-lasting plastic changes, lasting from hours to days. Although AMPA and kainate receptors mainly contribute to sensory transmission, NMDA receptors can mediate long-term plastic changes. Excitatory synapses contain an electron-dense thickening in the postsynaptic membrane, known as the postsynaptic density, containing receptors and their interacting proteins, including membrane-associated guanylyl kinase proteins. One main feature of NMDA receptors is their voltage-dependence. At resting membrane potentials, NMDA receptors are inactive because of pore blockade by extracellular Mg 2+, even in the presence of glutamate. Thus, to activate NMDA receptors at synapses, two events need to happen simultaneously. First, glutamate needs to be released and then bind to NMDA receptors; second, the postsynaptic membrane requirements to be depolarized so that extracellular Mg 2+ blockage can be removed. NMDA receptor-mediated calcium influx from the extracellular space into the postsynaptic cells then activates a series of signaling molecules within postsynaptic cells, including protein kinase, protein phosphatases, immediate early genes (i.e. genes that can be activated rapidly, or third messengers), as well as enzymes producing diffusible retrograde messengers. This unique property of NMDA receptors makes them the best candidates for mediators of memory formation in the brain. In learning-related central nuclei, such as the hippocampus and neocortex, synaptic potentiation or long-term potentiation, is NMDA-receptor-dependent. Inhibition of NMDA receptor function pharmacologically or genetically causes memory defects, and enhancing NMDA receptors leads to the superior performance of animal in various memory tests. 16