Snapshot: Pain Perception Snapshot: Pain Tracey Irene 2 1

Home , Nociception

hypothalamus) Inﬂuences from Inﬂuences from Excitatory (glutamate, substance P) Inhibitory (endogenuous opioids, GABA) higher brain centers (e.g., ACC, amygdala, +/- RVM PAG Anxiety Depression Expectation Happiness Attention Beliefs Learning and Conditioning Sensitisation Genetics Etc. Pain experience modulated by: wind-up 5HT2/3 5HT2/3 5HT1 BRAINSTEM CAV Alpha2 Central sensitization 5HT 5HT Insular Descending pain modulatory system

Sensory Gabapentin Anti-depressants inhibitory Spinal opioids MOR VLFPC Supraspinal opioids Brainstem Noradrenaline DLFPC Diminished pain Distraction/placebo RACC Thalamus MACC Spinal cord +/- RVM S1 Amygdala Thal Insular Hippo Insula/S2 Pain experience PAIN NEURAXIS PAIN Amy Sensory NAc MACC RACC Hypo Brainstem DLFPC facilitatory Heightened pain TO DORSAL HORN DLPFC SPINOTHALAMIC OFC SPINORETICULAR Injury/central sensitization VLPFC SPINOMESENCEPHALIC VMPFC RACC Thalamus FLEXIBLY ACCESSIBLE BILATERAL NETWORKS ACCESSIBLE BILATERAL FLEXIBLY MACC ATP P2X Protons Insular 2 LAIC Nociceptive drive Limb Mechanoreceptor Capsaicin MACC Heat/protons + K ATP P2Y TRPV1 ASIC Heightened pain 2 Hippocampus 2+ Nociception B Ca VAIC PAIN NEURAXIS PAIN Anxiety/negative expectation GPCRs + ) Na and Anthony Dickenson RACC VMPFC Thalamus 1 PG Na Bk EP Alpha-1 yelinated Ligand trkA M A ﬁbers (A δ LESS MORE NGF Unmyelinated ACTIVE ACTIVE NSAIDs Lidocaine Nociceptors detect extremes in Nociceptors detect extremes Transduction: chemicals temp, pressure, Nav receptors that send electrical Nav receptors Transmission: signals to the CNS Transducer small diameter axons (C ﬁbers) Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK London WC1E 6BT, University College London, Gower Street, Physiology and Pharmacology, Neuroscience, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford OX3 9DU, UK 9DU, OX3 Oxford Oxford, of University of the Brain, Resonance Imaging Functional Magnetic for Centre Oxford SnapShot: Pain Perception SnapShot: Pain Tracey Irene 2 1

1308 Cell 148, March 16, 2012 ©2012 Elsevier Inc. DOI 10.1016/j.cell.2012.03.004 See online version for legend and references. SnapShot: Pain Perception Irene Tracey1 and Anthony Dickenson2 1Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford OX3 9DU, UK 2Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK

Pain is an “unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (http://www.iasp-pain.org). Without a conscious brain, there is no pain. Chronic pain, as opposed to acute pain, is an enormous medical burden, with up to 20% of the adult population suffering; it ruins rather than saves lives and is associated with common comorbidities of sleep problems, depression, and fear. Better treatments are needed, as many patients live with unbear- able pain associated with appreciable suffering and healthcare and socioeconomic costs, along with reduced life expectancy. Pain is a complex, multidimensional experience that defied our understanding for centuries.

The Pain Neuraxis: Nociception The figure on the left illustrates a typical, “acute,” and normal human pain experience. The organism suffers an injury (in this case, being hit by a hammer), and “signals” travel from the site of injury to the spinal cord (the nociceptive drive), where they are relayed to a conscious brain that processes the information further and generates an experience that we describe as painful. However, nociception is defined as the “neural process of encoding noxious stimuli,” wherein a noxious stimulus is something that is “damaging or threatens damage to normal tissues, but pain sensation does not necessarily occur nor is it implied” (http://www.iasp-pain.org). Specialized peripheral sensory neurons (nociceptors) innervating the cutaneous system, as well as muscle, viscerae, and other organs, alert us to potential harm by detecting extremes in temperature, pressure, and injurious chemicals and, via transduction and then transmission, send electrical signals to the central nervous system, which might be interpreted as painful by the brain. Most nociceptors are either unmyelinated small diameter axons (C fibers) or myelinated A fibers with conduction velocities in the Aδ range. Their central processes project to superficial laminae I and II (C fiber) and I and V (Aδ) of the dorsal horn (Todd, 2010). Most nociceptors are polymodal, presumably providing necessary pain redundancy to the organism. But sufficient functionally distinct cutaneous nociceptors allow biological organisms a rich diversity of pain qualities (Basbaum et al., 2009) (see inset box on left). The result of these discoveries is that we have new opportunities for novel therapies targeting nociception right at its source. From the dorsal horn (middle inset), there are three major projection pathways to the brain: spinothalamic (dorsal horn to thalamus and onto cortex) mainly from neurons with wide dynamic range properties encompassing innocuous through to noxious stimuli; spinoreticular (dorsal horn to reticular formation of medulla and pons then onto thalamus and cortex); and spinomesencephalic (dorsal horn to PAG of brainstem). The figure on the right illustrates that, as peripheral inputs arrive in the spinal cord, projection neurons and interneurons integrate these inputs, and local circuits—both excitatory and inhibitory—interact to allow for bidirectional changes in spinal outputs. Excitatory transmitters such as glutamate and substance P can facilitate and “wind up” neuronal responses, whereas inhibitory interneurons using endogenous opioids and GABA can modulate spinal activity. Furthermore, influences from the brain can again switch the level of spinal activity up or down (D’Mello and Dickenson, 2008).

The Brainstem and Descending Pain Modulation The brainstem plays a pivotal role within the descending pain modulatory system (DPMS), a system that regulates nociceptive processing within the dorsal horn of spinal cord transmission and, thereby, which signals enter the brain (see figure on right). The brainstem’s component of the DPMS involves, among other nuclei, the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM), which is the final common output for descending influences from rostral brain sites. Importantly, there is bidirectional central control of nociception that could either alleviate pain in situations in which antinociception is necessary for survival (−), as in sporting competition or battle, but could also facilitate nociceptive processing and thereby contribute to the maintenance of heightened pain states (+) (Fields, 2000). Intriguingly, postinjury, an imbalance between descending inhibitory and facilitatory influences is key for maintaining chronic pain states and central sensitization, a key dorsal horn event that amplifies incoming nociceptive inputs (De Felice, et al., 2011) (see figure on right). Why these systems are abnormal in some individuals is a focus of current research. The anterior cingulate cortex, amygdalae, and hypothalamus are also part of the DPMS, but within the human brain, there are likely more regions to be included, as subcortical and cortical connections to the brainstem are a likely basis by which cognitive and emotional variables interact with nociceptive processing to influence the resultant pain experienced. Altered or interrupted function in the DPMS may be why pain alters sleep, mood, and other central processes mediated by these structures. The DPMS release the monoamines, noradrenaline (NA), and 5HT on to spinal circuits. Not only do RVM neurons both facilitate and inhibit spinal functions and can be con- trolled by brainstem opioid receptors, but the receptors for these monoamines allow top-down activity to likewise enhance or reduce spinal neuronal activity. NA acts through its inhibitory α2 adrenoceptor to inhibit, whereas 5HT has bidirectional effects, inhibiting via 5HT-1 receptors (targets for triptans in headache) and facilitating when 5HT-2 or 5HT-3 receptors are activated at spinal levels.

Pain Neuraxis: Pain Experience and Its Modulation The spinal cord relays nociceptive information to specific thalamic nuclei (e.g., VPL, VPM, VMpo, and MDvc) and from there to a flexibly accessible network of brain regions (see middle figure and top panels). In parallel, the lateral nuclei communicate nociceptive information to areas of the cortex involved in sensory-discriminatory aspects of pain, whereas the medial nuclei communicate nociceptive information to areas of the brain involved in attentional, emotional, and decision-making aspects of pain perception. The emergent and combined bilateral activity—more active on the contralateral side to input—produces the multidimensional experience that is pain—an emergent, malleable experience rather than a single, static entity. Processing within the central nervous system is subject to many influences, from periphery to spinal cord to brain, as detailed; so although nociception can lead to a pain experience, the relationship is highly nonlinear, making diagnoses difficult. Based upon somatotopic- and modality-specific representa- tion for nociceptive inputs, a “nociceptive cortex” within the operculo-insula region is being postulated, akin to other major senses, but there is likely no simple “pain cortex.” Brain regions found active across a range of human pain imaging studies include: thalamus; mid/rostral anterior cingulate cortex; primary and secondary somatosensory cortex; anterior, mid, and posterior divisions of the insular cortex; dorsal, mid, and ventral prefrontal cortices; and brainstem nuclei and parts of the basal ganglia (Tracey, 2011). This combined set of brain regions is often referred to as the “pain matrix,” as illustrated in middle figure, and likely serves to: (1) determine what, where, and how intense the pain is, (2) attend to and make decisions about its threat so an appropriate behavioral response can occur, and (3) learn what caused it for future avoidance and learning. However, it is apparent from the middle figure that other regions (e.g., amygdala, hippocampus, and cerebellum) can also be activated, dependent on the mood, cognitive state, and context of the individual. The magnitude of activity within each region can variably alter too, providing an additional means by which the pattern changes to produce altered experiences. As these brain regions contribute to other human experiences, it remains a mystery as to why their concerted activation produces an unequivocal sensation that hurts, which we call pain. The upper-left panel illustrates how heightened pain reports due to negative expectations and anxiety is mediated by a change in activity within a specific region, the hippocampus, which subsequently produces increased activity within core pain processing regions without any concomitant change in peripheral nociceptive input (Tracey, 2010). This is contrasted with the upper-middle panel, which shows heightened pain report postinjury but this time is due to involvement of the DPMS and central sensitization (Tracey, 2011). The upper-right panel illustrates a decreased pain experience, without any change in peripheral nociceptive input, due to distraction or placebo effects. Here, certain regions mediate the effect (higher activity shown in orange), producing less activity in core pain regions (less activity shown in red).

Management of Chronic Pain States Alongside the multiple genetic, cellular, chemical, and inflammatory changes that occur postinjury to generate the abnormal pain states experienced by patients, failure to nor- mally resolve central sensitization, which is a normal, adaptive response postinjury, is a key factor that contributes to the maintenance of chronic pain states. Further, centers of the brain that are important in emotional and aversive responses to pain constitute mostly monoamine pathways that can descend to facilitate spinal mechanisms, providing the interplay between sensory and psychological events. The importance of some of these systems is validated by mechanisms of action of analgesics (Ban- nister et al., 2009; Dickenson, et al., 2002). Local anesthetics block sodium channels at their site of application and thus prevent incoming messages. Some antiepileptics such as carbamazepine share this action, whereas others such as gabapentin and pregabalin modulate transmitter release at spinal levels. Opioids, through their inhibitory receptors, also reduce spinal transmitter release but damp down spinal neuronal activity and work in the brain to switch descending facilitations off and turn inhibitions on. Antidepressants act to increase the levels of noradrenaline and 5HT and thus directly modulate descending controls to reduce pain; this is often independent of their effects on mood.

1308.e1 Cell 148, March 16, 2012 ©2012 Elsevier Inc. DOI 10.1016/j.cell.2012.03.004 SnapShot: Pain Perception Irene Tracey1 and Anthony Dickenson2 1Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford OX3 9DU, UK 2Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK

Abbreviations S1/S2, primary/secondary somatosensory cortices; DLPFC, dorsolateral prefrontal cortex; VLPFC, ventrolateral prefrontal cortex; VMPFC, ventromedial prefrontal cortex; OFC, orbitofrontal cortex; MACC, medial anterior cingulate cortex; RACC, rostral anterior cingulate cortex; Thal, thalamus; Cerbllm, cerebellum; PAG, periaqueductal gray; RVM, rostroventromedial medulla; NAc, nucleus accumbens; Hypo, hypothalamus; Hippo, hippocampus; Amy, amygdala; GPCR, G protein-coupled receptor; LAIC, ligand-activated ion channel; VAIC, voltage-activated ion channel.

References

Bannister, K., Bee, L.A., and Dickenson, A.H. (2009). Preclinical and early clinical investigations related to monoaminergic pain modulation. Neurotherapeutics 6, 703–712.

Basbaum, A.I., Bautista, D.M., Scherrer, G., and Julius, D. (2009). Cellular and molecular mechanisms of pain. Cell 139, 267–284.

D’Mello, R.D., and Dickenson, A.H. (2008). Spinal cord mechanisms of pain. Br. J. Anaesth. 101, 8–16.

De Felice, M., Sanoja, R., Wang, R., Vera-Portocarrero, L., Oyarzo, J., King, T., Ossipov, M.H., Vanderah, T.W., Lai, J., Dussor, G.O., et al. (2011). Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. Pain 152, 2701–2709.

Dickenson, A.H., Matthews, E.A., and Suzuki, R. (2002). Eur. J. Pain 6, 51–60.

Fields, H.L. (2000). Pain modulation: expectation, opioid analgesia and virtual pain. Prog. Brain Res. 122, 245–253.

Todd, A.J. (2010). Neuronal circuitry for pain processing in the dorsal horn. Nat. Rev. Neurosci. 11, 823–836.

Tracey, I. (2010). Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. Nat. Med. 16, 1277–1283.

Tracey, I. (2011). Nat. Rev. Neurol. 7, 173–181.