AACN Clinical Issues Volume 16, Number 3, pp. 277–290 C 2005, AACN

The Physiology and Processing of Pain A Review

Cynthia L. Renn, RN, PhD, ACNP; Susan G. Dorsey, RN, PhD

6 visits to a healthcare provider4 and the American Academy of Pain Management Despite the many advances in our reports5 that uncontrolled pain is at epidemic understanding of the mechanisms proportions, with 50 million Americans suf- underlying pain processing, pain fering from some form of chronic pain and continues to be a major healthcare another 25 million experiencing acute pain problem in the United States. Each day, caused by accident or surgical procedures millions of Americans are affected by both each year. Studies6–8 estimate that 70 million acute and chronic pain conditions, costing visits to healthcare providers were motivated in excess of $100 billion for by pain and that 4.9 million people visited a treatment-related costs and lost work healthcare provider for treatment of chronic productivity. Thus, it is imperative that pain, all at an estimated cost exceeding $100 better treatment strategies be developed. billion. Further, pain patients and their fami- One step toward improving pain lies suffer from intangible costs related to the management is through increased pain, such as decreased quality of life, de- knowledge of pain physiology. Within the pression, and interpersonal stresses.9 , there are several Pain not only affects patients and their pathways that transmit information about families, but also society and the economy pain from the periphery to the brain. There as well. Beyond the cost of medical treat- is also a network of pathways that carry ment, society bears the costs of increased modulatory signals from the brain and healthcare utilization and lost productivity that alter the incoming flow of by patients in pain. More than two thirds pain information. This article provides a of those living with chronic pain have had review to the physiology and processing of their pain for 5 or more years, often pro- pain. (KEYWORDS: ascending pain ducing significant limitations on daily activ- pathways, descending modulation, pain, ity, and it is estimated that 36 million Amer- ) icans missed nearly 4 billion work days due to pain, resulting in a substantial loss of work

Congress declared the years of 2000 to 2010  as the Decade of Pain Control and Research, From the Department of Organizational Systems and yet pain continues to be a leading public Adult Health, School of Nursing, University of Maryland, health and nursing problem in the United Baltimore, Maryland. States.1 Pain is the principal symptom caus- Reprint requests to Cynthia L. Renn, Assistant Profes- sor, University of Maryland School of Nursing, Depart- ing patients to seek medical attention, affect- ment of Organizational Systems and Adult Health, 3rd 2,3 ing 1 in 5 Americans on any given day. Floor, 655 West Lombard Street, Baltimore, MD 21201– It is estimated that pain accounts for 1 in 1579 ([email protected] ).

277 278  RENN AND DORSEY AACN Clinical Issues productivity and an estimated cost of $65 bil- of the pain experience led McCafferey15 to lion annually.7 define pain as “whatever the experiencing A critical step toward minimizing the phys- person says it is, existing whenever the ex- ical, emotional, and financial drain on pa- periencing person says it does.”(p7) Pain has tients and caregivers is improving the clin- further been defined by the International As- ical management of pain. When managing sociation for the Study of Pain (IASP)10 as the care of a patient with pain, the advanced “an unpleasant sensory and emotional expe- practice nurse must work together with the rience associated with actual or potential tis- patient to establish a common treatment goal. sue damage or described in terms of such In many cases, the goal of the treatment strat- damage.”(p250) egy may be to achieve maximal analgesia Twobroad categories of pain, acute and (the absence of a pain response to a nox- chronic, are seen in the clinical setting. Un- ious stimulus).10,11 However, when maximal der these broad categories fall the subtypes analgesia is not possible, the treatment goal of pain, which include inflammatory, neuro- shifts to reducing the pain to a level that the pathic, cancer, etc. Acute pain tends to be of patient finds tolerable and allows for the per- a short duration, typically has an identifiable formance of normal activities of daily living. cause, and is focal to the site of injury.10–13,16 Upon establishment of the treatment goal, the Further, acute pain functions as an endoge- next step is to develop a plan to meet that nous protective mechanism that signals the goal. A key factor that aids in the process brain of the occurrence of real or poten- of selecting the most appropriate treatment tial tissue injury, thus prompting a protective modalities, in addition to a thorough pain response.12 Clinically, acute pain functions as assessment, is an in-depth understanding of a symptom, tends to be self-limited, and gen- pain physiology. A thorough understanding erally responds to a straightforward treatment of how pain is processed at each stage in plan with a good to excellent prognosis.16 the peripheral and the central nervous sys- However, pain can persist beyond the point tems allows the treatment strategy to be tai- of tissue healing and develop into a chronic lored to meet the needs of the individual and debilitating state. Chronic pain is unre- patient. This article provides a primer on ma- lenting, has no identifiable cause, spreads be- jor structures and processes involved in pain yond the original site of injury, and serves no physiology. biological function.10–13,16 Clinically, chronic pain has the characteristics of a disease state, can produce psychological disturbances, re-  What Is Pain? quires complex treatment strategies, and typ- ically has a poor prognosis.16 When a region of the body is exposed to a tissue-damaging or potentially tissue-  Pain Transmission: The Ascending damaging insult, one experiences the un- pleasant sensation of pain.12 Pain has been Pain Pathways described as a multifaceted and highly sub- jective experience that is unique to each The ascending pain pathways transmit noci- person. Pain is not only influenced by phys- ceptive information from peripheral tissues to iological processes, but also influenced by the cerebral cortex for interpretation as pain. psychological and emotional processes as The ascending pathways are complex struc- well. It has been reported that the inten- tures, involving both the peripheral (PNS) sity of pain can be influenced by contex- and central nervous systems (CNS). tual cues. For example, similar types of trau- matic injury may be seemingly painless in Nociception certain situations and extremely painful in others.13,14 This phenomenon was first de- Nociception, the initial processing of pain, scribed by Beecher,13 who found that soldiers involves a system of mechanisms that en- with severe wounds often reported little pain code and transmit the pain signal, along the while civilians with similar injuries typically ascending pathway, from the point of nox- reported severe pain. The subjective nature ious stimulation in the periphery to higher Vol. 16, No. 3, July-Sept 2005 PAIN PROCESSING  279

Figure 1. Ascending pain pathway. The ascending pain pathway transmits nociceptive information from peripheral tissues (1) via a primary afferent fiber, which enters the in the dorsal horn (2) where it with a second-order . The second-order neuron travels up through the spinal cord (3) and brainstem, synapsing in the tha- lamus with a third-order neuron that transmits the nociceptive information to the brain (4) for interpretation as pain. Adapted with permission from Fields and Basbaum.63(p310) centers in the CNS, including the cerebral nociceptors, a number of endogenous chemi- cortex where an awareness of the presence cals have been identified that can activate no- of pain occurs12 (see Figure 1). The first ciceptors, including potassium, bradykinin, step in the complex pain process is the serotonin, histamine, prostaglandins, and transduction of a noxious stimulus (nocicep- others.19–23 tion) by specialized (nociceptors).17,18 Nociceptors are found in most organs and tissues in the body and are activated by ei- Spinal Dorsal Horn ther a noxious mechanical (touch or pres- When a noxious stimulus is transduced by a sure), thermal (hot or cold), or chemical (en- , a signal is generated that is trans- dogenous or exogenous) stimulus12,17,18 (see mitted as an electrical action potential along Figure 2). The term noxious is applied small diameter A-delta (myelinated, fast to nociceptive stimuli because nociceptors transmission, sharp or pricking first pain)24,25 are activated in response to strong stim- and C (unmyelinated, slow transmission, dull uli that fall in the tissue-damaging range, or burning second pain)25,26 primary affer- whereas nonnociceptive mechanoreceptors, ent nerve fibers to the gray matter of the thermoreceptors, and chemoreceptors re- spinal cord (see Figure 2 inset). On cross- spond to milder stimuli that fall in a range section, the spinal gray matter forms a but- below the tissue-damaging level.12,17,18 In ad- terfly shape and can be divided into 10 lami- dition to exogenous chemicals that stimulate nae, or layers, which are numbered I through 280  RENN AND DORSEY AACN Clinical Issues

Figure 2. Pain transmission from peripheral tissues to the spinal cord. Noxious stimuli (thermal, chemical, or mechanical) that are applied to peripheral tissues activate nociceptors that are located within the tissues. The stimulus is transduced by the nociceptor to generate a nociceptive signal that is transmitted as an action potential along a primary afferent nerve to the dorsal horn of the spinal cord. Within the primary afferent nerve (inset), the signal can be transmitted rapidly by myelinated A-delta fibers or more slowly by unmyelinated C fibers. The dorsal root is part of the primary afferent nerve, located near the spinal cord, and contains the cell bodies of all fibers traveling within the nerve.

IX, from dorsal to ventral, with X surround- tract in both the rostral (toward the nose) and ing the central canal18,27,28 (see Figure 3). caudal (toward the tail) directions. As the pri- Pain processing occurs predominantly in mary afferents travel in Lissauer’s tract, they laminae I, II, and V.18,28 send collateral projections to the gray matter The primary afferent fibers enter the spinal along the entire 4 to 6 segment length,12,29,30 cord in the dorsolateral aspect of the gray thus transmitting the pain signal over a broad matter (the dorsal horn) through the dorsal area of the spinal cord rather than to a dis- root. Upon entering the dorsal horn, the pri- crete location (see Figure 4). This is impor- mary afferents bifurcate in a “T” pattern and tant in the case of spinal pathology, such as travel 2 to 3 spinal segments within Lissauer’s a lesion, which could block the signal if it is

Figure 3. Structure of the spinal cord. The gray matter is a butterfly-shaped area in the center of the spinal cord. The gray matter contains unmyelinated nerve fibers and the cell bodies of the . The spinal gray matter is surrounded by , which is composed of myelinated nerve fibers. The is a conduit for cerebral spinal fluid and runs the full length of the spinal cord. The spinal gray matter has two dorsal and two ventral horns. The dorsal horns, comprising the dorsal aspect of the gray matter bilaterally, are primarily responsible for receiving and transmitting sensory information. The ventral horns, comprising the ventral aspect of the gray matter bilaterally, are primarily responsible for sending motor information out to the periphery. Based on cellular organization, the gray matter can be divided into ten laminae (layers), which are numbered I-IX from dorsal to ventral. Lamina X surrounds the central canal. Vol. 16, No. 3, July-Sept 2005 PAIN PROCESSING  281

order neurons further process the nocicep- tive signal and transmit it to cortical and lim- bic structures, where the signal is interpreted as pain.12 The organization of and the neuroanatomy within the ascending pain pathways are quite complex.17,18,34,35 The most prominent and well-described of the ascending pathways is the (STT—spinal cord to thalamus), which is thought to trans- mit sensations of pain, temperature, and touch.12,17,18 The majority of the projection neurons that travel in the STT originate in the superficial laminae I and II and deeper lamina V of the spinal dorsal horn.36,37 Be- Figure 4. Lissauer’s tract and primary afferent collat- fore ascending, the STT neurons decussate eralization in the spinal cord. The primary afferent fiber (cross midline) through the ventral white (PAF) enters the spinal dorsal horn and the nerve fibers commissure (junction between two parts) to bifurcate in Lissauer’s tract. After bifurcation, the nerve the opposite ventrolateral quadrant of the fibers travel 2–3 spinal segments in both the rostral and spinal cord white matter, where they ascend caudal directions. Throughout the length of travel in Lis- sauer’s tract, the afferent nerve fibers send out collat- in the ventrolateral (VLF—bundle 12,36,37 eral projections into the dorsal horn to transmit the pain of nerve fibers) to the thalamus (see signal across multiple segments of the spinal cord. Figure 6a). A second prominent ascending pathway that is involved in pain transmis- sion is the spinomesencephalic tract (SMT— transmitted to a discrete location within the spinal cord to mesencephalon), which origi- area of pathology. nates in laminae I, II, and V of the spinal dor- In the dorsal horn, the primary afferent sal horn, decussates, and also travels in the fibers (connect), either directly or in- VLF to the mesencephalon (also known as directly (via ), with second-order the midbrain)12,36,38,39 (see Figure 6b). Within projection neurons and convey the nocicep- the midbrain, the neurons in the SMT termi- tive message through the release of a vari- nate in several areas, such as the periaque- ety of neurotransmitters, such as the exci- ductal gray (PAG) and nucleus cuneiformis, tatory amino acid glutamate or the peptide among others.18,39–41 A third tract that has substance P12,31,32,33 (see Figure 5). After the also been shown to convey nociceptive in- nociceptive signal has been received in the formation is the spinoreticular tract (SRT— dorsal horn, the information is transmitted spinal cord to ), which to higher centers in the CNS by projection terminates in the reticular formation of the neurons.17,18,34,35 medulla12,17,18 (see Figure 6c). Though each ascending tract has a primary target structure, they also send collateral projections to other Ascending Tracts areas of the brainstem as they pass through. The projection neurons transmit the noci- When the projections from the spinal cord ceptive signal rostrally along the ascend- reach their targets, they synapse with third- ing pathways in the spinal cord to vari- order neurons that serve as relays and project ous supraspinal structures in the brainstem to other regions within the brainstem, dien- and diencephalon, including the medullary cephalons, and forebrain.12,17 While the three reticular formation, periaqueductal gray, pathways described above are thought to parabrachial region, hypothalamus, thala- be the predominant pathways involved in mus, and various limbic structures.17,18,34,35 pain transmission, they do not constitute a The function of the ascending pathways is complete list of all ascending sensory path- simply the transmission of the nociceptive ways. A detailed description of the remain- information. Within the supraspinal target ing pathways is beyond the scope of this structures of the ascending pathways, third- review. 282  RENN AND DORSEY AACN Clinical Issues

Figure 5. Synapse of the primary afferent fiber with a projection neuron in the dorsal horn. The primary afferent fiber (PAF) enters the spinal dorsal horn and synapses (A) directly with a projection neuron (PN; second-order neuron) or (B) with an (IN) that then synapses with a projection neuron. The pain signal is transmitted across the synapse by the release of neurotransmitters from the presynaptic neuron that cross the synaptic cleft and bind with receptors on the postsynaptic neuron.

Thalamus and transfer of ascending nociceptive infor- The thalamus is thought of as the major mation to the cerebral cortex.18,42 As such, supraspinal relay structure for the integration the thalamus not only receives input from the

Figure 6. Ascending transmission tracts. (A) Spinothalamic tract (STT). The projection neurons that form the STT originate predominantly in laminae I, II, and V of the spinal dorsal horn. The STT neurons decussate (cross midline) through the ventral white commissure to the opposite ventrolateral quadrant of the spinal cord. In the ventrolateral quadrant, the STT neurons ascend from the spinal cord to the thalamus in the ventrolateral funiculus (VLF; bundle of fibers). (B) Spinomesencephalic tract (SMT). The neurons that form the SMT also originate predominantly in laminae I, II, and V of the dorsal horn. The SMT neurons decussate through the ventral white commissure to the VLF, where they ascend from the spinal cord to the mesencephalon and terminate in several structures such as the periaqueductal gray (PAG). (C) Spinoreticular tract (SRT). The SRT neurons originate predominantly in laminae I, II, and V of the dorsal horn, decussate through the ventral white commissure to the VLF and ascend from the spinal cord to the reticular formation of the medulla. Adapted with permission from Fields and Basbaum.63(p310) Vol. 16, No. 3, July-Sept 2005 PAIN PROCESSING  283

STT, but it also receives input from collateral research into the contribution of supraspinal projections sent out of the other ascending structures to nociceptive modulation showed tracts that carry nociceptive information.18,42 that the mammalian CNS has several well- Within the thalamus, nociceptive informa- defined, supraspinally organized descending tion regarding the type, temporal pattern in- pathways. These pathways form a network of tensity, and topographic localization of the neural systems that modulate the ascending pain is encoded prior to sending the informa- transmission of nociceptive information, with tion onward to limbic structures and cortical the most well-described being the circuitry sites.12,18,42 mediating the brainstem control of nocicep- tive transmission at the level of the spinal dor- sal horn.53–63 Cerebral Cortex The effects of descending modulation are exerted in the spinal dorsal horn on Ultimately, the nociceptive signal reaches the the synapse between the primary afferent cerebral cortex where it is integrated and un- and projection neurons or on interneurons dergoes cognitive and emotional interpreta- that synapse with projection neurons (see tion as stemming from a painful stimulus.12,43 Figure 7). This synapse in the dorsal horn The nociceptive signal is transmitted from is the point where nociceptive information the thalamus to a variety of cortical sites: is first integrated before being transmitted the somatosensory S1 area and S2 area, the to higher centers in the CNS.12,18,54,64 The insular cortex, the anterior cingulate cortex, descending modulatory effect is applied ei- and the medial prefrontal cortex.44–48 Within ther by inhibiting the release of neurotrans- these cortical regions, there is a complex mitter from the primary afferent fiber (see network of interconnections that include the Figure 7A) or by inhibiting the function thalamus and limbic structures.49 This net- of neurotransmitter receptors on the post- work of cortical structures is responsible for synaptic neuron (see Figure 7B). Several the sensory-discriminative (perception of the supraspinal sites are known to contribute intensity, location, duration, temporal pat- to the descending modulation of noci- tern, and quality of noxious stimuli) and ception, either directly (sending projection motivational-affective (relationship between neurons to the spinal cord) or indirectly pain and mood, attention, coping, tolerance, (sending projection neurons to other re- and rationalization) components of the pain gions in the brainstem that send projec- experience.12,50,51 tions to the spinal cord). These include the PAG, locus coeruleus (LC), and the  Descending Modulation of rostral ventromedial medulla (RVM) among Nociception others.12,54,63,65,66

The idea that pain undergoes modulatory ef- Periaqueductal Gray fects from higher areas of the CNS was first introduced by Head and Holmes.52 Over the The PAG is a midline structure, composed of past century, a large volume of information densely packed heterogeneous neurons, that has been learned regarding pain perception surrounds the cerebral aqueduct through- and modulation. Thus, much effort has been out the mesencephalon67,68 (see Figure 8). put into understanding the mechanisms in- It has been well established that the PAG volved in the modulatory process.53–55 is a major component of the pain modula- Several decades after Head and Holmes52 tory circuitry, since Reynolds53 first reported first theorized that pain is under the influ- the phenomenon of stimulation produced ence of higher areas in the CNS, studies con- analgesia after performing abdominal surgery firmed their theory by providing evidence on an unanesthetized rat while electrically that a number of supraspinal sites contribute stimulating the PAG.59,69 Given that few PAG to the control of ascending sensory input efferents project directly to the spinal dor- by exerting tonic inhibitory control of neu- sal horn,70–72 researchers have focused on rons in the spinal dorsal horn.56–58 Further discovering other pathways that mediate the 284  RENN AND DORSEY AACN Clinical Issues

Figure 7. Effect exerted by a descending modulatory projection neuron on the synapse between a primary afferent fiber and a projection neuron in the dorsal horn. The descending modulatory projection neuron can exert its effect by inhibiting the release of neurotransmitters from the primary afferent fiber (PAF) in the spinal dorsal horn (A) or by inhibiting neurotransmitter receptors on the ascending projection neuron (PN; B), thus altering the flow of nociceptive information to the brain. spinal effects of PAG stimulation. It was tralateral spinal dorsal horn laminae I, II, found that the modulatory effect of the PAG and V where they exert an antinociceptive is exerted indirectly through efferent connec- effect.79–81 In addition to the intrinsic antinoci- tions with a variety of brainstem structures, ceptive effects of the pontine noradrener- such as the RVM, parabrachial nucleus, locus gic cell groups, they also receive neuronal coeruleus, and the A5 and A7 noradrenergic projections from the RVM and PAG, thus cell groups.73–78 serving as relays for the modulatory effects from the RVM and PAG to the spinal dorsal LOCUS COERULEUS: The LC is a bilateral struc- horn.82,83 ture, composed of noradrenergic neurons, that is located in the pons on the border of Rostral Ventromedial Medulla the fourth cerebral ventricle79 (see Figure 9). Bilateral projections from the LC and nearby The RVM has been studied at length and A7 cell group descend primarily to the con- is recognized as a major component of the

Figure 8. The periaqueductal gray (PAG). The PAG Figure 9. The locus coeruleus (LC). The LC is a bi- is a midline structure that surrounds the cerebral aque- lateral structure that is adjacent to the fourth ventricle duct in the mesencephalon of the brainstem. in the pons of the brainstem. Vol. 16, No. 3, July-Sept 2005 PAIN PROCESSING  285

Figure 10. The rostral ven- tromedial medulla (RVM). The RVMisaregion of the ventral medulla that includes the midline nucleus raphe magnus (NRM), gigantocellularis pars alpha (GiA) and lateral paragigantocellularis (LPGi).

pain modulatory circuitry, exerting its own idence demonstrate time-dependent bipha- modulatory effects in addition to relaying sic properties of the pain modulatory system the modulatory effects from higher brainstem that can both inhibit and facilitate nocicep- sites.54,84,85 It is a large region of the medulla tive transmission.97,100,103–108 However, many that includes the midline nucleus raphe mag- aspects of the underlying mechanisms of no- nus (NRM) and portions of the adjacent retic- ciceptive modulation and the shift from facil- ular formation; the nucleus reticularis gigan- itation to inhibition remain unclear. tocellularis pars alpha (GiA) and the nucleus The RVM is one area in the pain mod- paragigantocellularis lateralis (LPGi) (Figure ulatory system that puts forth opposing 10). Efferent projections from the RVM ex- modulatory effects and is a crucial site tend bilaterally, have been identified in all for balancing descending modulation. When levels of the spinal cord, and comprise a activating the descending pathways that orig- major portion of the neurons projecting to inate in the RVM, the resulting effect (in- the spinal dorsal horn.61,62,86–90 These neurons hibitory or facilitatory) is dependent on have widely collateralized yet lamina-specific the intensity and nature of the intra-RVM projections,91 with dense bilateral termina- stimulus.106–108 Although the circuitry respon- tions in laminae I, II, and V of the spinal sible for generating facilitatory and inhibitory cord dorsal horn.63,92,93 While all of the com- modulation may be distinct, an anatom- ponents of the descending modulatory net- ical and neurochemical differentiation of work are important, the PAG and RVM have the bimodal modulatory structures has not been shown to play key roles in the under- been determined.97,103,104,106,109 However, sev- lying mechanisms of pain modulation.54,63,85 eral studies that used either electrical stimula- Further, the PAG to RVM projection is criti- tion or lesions have shown opposing modu- cal for the PAG to exert its descending mod- latory effects from the different subregions of ulatory effect on dorsal horn nociceptive the RVM.107,109,110 The effects of both descend- neurons.76,84,93,94 ing inhibition and facilitation have been ob- The RVM exerts its modulatory effect served during multineuron recording in the on nociceptive transmission at the spinal dorsal horn, where it has been shown that level, producing antinociception to painful neighboring neurons are simultaneously un- stimuli.73,74,95 During persistent noxious stim- der facilitatory and inhibitory control from ulation, such as during a prolonged inflam- supraspinal structures.111 The balance be- matory state, there is continued activation of tween inhibition and facilitation determines the descending pain modulatory circuitry and the net effect of descending modulation on increased neuronal activity in the RVM that nociceptive transmission.18,34,110,112 results in a progressive enhancement of de- In summary, the processing of pain is a scending modulation of spinal nociceptive complex phenomenon, involving both the transmission.96–102 peripheral and central nervous systems. No- ciceptive information regarding actual or po- tential tissue injury is transmitted from pe- Biphasic Modulation ripheral nerve endings (nociceptors), via a The descending modulation of nociception complex series of ascending pathways, to is not wholly inhibitory. Several lines of ev- the brain. Within the brain, the nociceptive 286  RENN AND DORSEY AACN Clinical Issues signals are further processed in the so- plan that is appropriate for each individual matosensory cortex and interpreted as pain. patient. As the ascending nociceptive information passes through the brainstem and reaches the brain, it triggers the activation of a net- References work of brainstem structures and pathways that exert a modulatory effect on nociceptive 1. Nelson R. Decade of pain control and transmission. The structures involved in pain research gets into gear in USA. Lancet. modulation send neuron projections from the 2003;362:1129. brainstem to the spinal dorsal horn where 2. 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