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The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC-posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain.

Scientific evidence supports the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation, and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory, and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. In addition, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

We report a novel model in which remote activation of peripheral nociceptive pathways in transgenic mice is achieved optogenetically, without any external noxious stimulus or injury. Taking advantage of a binary genetic approach, we selectively targeted Nav1.8(+) sensory neurons for conditional expression of channelrhodopsin-2 (ChR2) channels. Acute blue light illumination of the skin produced robust nocifensive behaviors, evoked by the remote stimulation of both peptidergic and nonpeptidergic nociceptive fibers as indicated by c-Fos labeling in laminae I and II of the dorsal horn of the spinal cord. A non-nociceptive component also contributes to the observed behaviors, as shown by c-Fos expression in lamina III of the dorsal horn and the expression of ChR2-EYFP in a subpopulation of large-diameter Nav1.8(+) dorsal root ganglion neurons. Selective activation of Nav1.8(+) afferents in vivo induced central sensitization and conditioned place aversion, thus providing a novel paradigm to investigate plasticity in the pain circuitry. Long-term potentiation was similarly evoked by light activation of the same afferents in isolated spinal cord preparations. These findings demonstrate, for the first time, the optical control of nociception and central sensitization in behaving mammals and enables selective activation of the same class of afferents in both in vivo and ex vivo preparations. Our results provide a proof-of-concept demonstration that optical dissection of the contribution of specific classes of afferents to central sensitization is possible. The high spatiotemporal precision offered by this non-invasive model will facilitate drug development and target validation for pain therapeutics.

Bodily injury in mammals often produces persistent pain that is driven at least in part by long-lasting sensitization and spontaneous activity (SA) in peripheral branches of primary nociceptors near sites of injury. While nociceptors have been described in lower vertebrates and invertebrates, outside of mammals there is limited evidence for peripheral sensitization of primary afferent neurons, and there are no reports of persistent SA being induced in primary afferents by noxious stimulation. Cephalopod molluscs are the most neurally and behaviorally complex invertebrates, with brains rivaling those of some vertebrates in size and complexity. This has fostered the opinion that cephalopods may experience pain, leading some governments to include cephalopods under animal welfare laws. It is not known, however, if cephalopods possess nociceptors, or whether their somatic sensory neurons exhibit nociceptive sensitization. We demonstrate that squid possess nociceptors that selectively encode noxious mechanical but not heat stimuli, and that show long-lasting peripheral sensitization to mechanical stimuli after minor injury to the body. As in mammals, injury in squid can cause persistent SA in peripheral afferents. Unlike mammals, the afferent sensitization and SA are almost as prominent on the contralateral side of the body as they are near an injury. Thus, while squid exhibit peripheral alterations in afferent neurons similar to those that drive persistent pain in mammals, robust changes far from sites of injury in squid suggest that persistently enhanced afferent activity provides much less information about the location of an injury in cephalopods than it does in mammals.

Pain, itch, heat, cold, and touch represent different percepts arising from somatosensory input. How stimuli give rise to these percepts has been debated for over a century. Recent work supports the view that primary afferents are highly specialized to transduce and encode specific stimulus modalities. However, cross-modal interactions (e.g. inhibition or exacerbation of pain by touch) support convergence rather than specificity in central circuits. We outline how peripheral specialization together with central convergence could enable spinal microcircuits to combine inputs from distinctly specialized, co-activated afferents and to modulate the output signals thus formed through computations like normalization. These issues will be discussed alongside recent advances in our understanding of microcircuitry in the superficial dorsal horn., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: This review summarizes the scientific literature addressing the effects of aging on pain processing in the brain., Design: A literature search was undertaken using PubMed and search terms including pain, aging, and brain., Settings and Patients: Studies including healthy older people and older people with painful disorders were reviewed., Measures: Publications reporting the outcomes of neuroimaging techniques including positron emission tomography, structural and functional magnetic resonance imaging, and electroencephalography in samples incorporating older people were reviewed., Results: Age-related decreases in regional brain volume occur in structures implicated in pain processing, and are most pronounced in the prefrontal cortex and hippocampus, whereas age-related atrophy in brainstem regions involved in pain modulation is less pronounced. Functional brain imaging has revealed decreased pain activation in the putamen and insula among older people during extrinsic stimuli, but any effects of aging on the processing of clinical pain are yet to be reported., Conclusions: The network of brain regions involved in pain processing are subject to age-related changes in structure, but that the functional implications of these changes are yet to be determined., (Wiley Periodicals, Inc.)

Cerebral cortical activity is heavily influenced by interactions with the basal ganglia. These interactions occur via cortico-basal ganglia-thalamo-cortical loops. The putamen is one of the major sites of cortical input into basal ganglia loops and is frequently activated during pain. This activity has been typically associated with the processing of pain-related motor responses. However, the potential contribution of putamen to the processing of sensory aspects of pain remains poorly characterized. In order to more directly determine if the putamen can contribute to sensory aspects of pain, nine individuals with lesions involving the putamen underwent both psychophysical and functional imaging assessment of perceived pain and pain-related brain activation. These individuals exhibited intact tactile thresholds, but reduced heat pain sensitivity and widespread reductions in pain-related cortical activity in comparison with 14 age-matched healthy subjects. Using magnetic resonance imaging to assess structural connectivity in healthy subjects, we show that portions of the putamen activated during pain are connected not only with cortical regions involved in sensory-motor processing, but also regions involved in attention, memory and affect. Such a framework may allow cognitive information to flow from these brain areas to the putamen where it may be used to influence how nociceptive information is processed. Taken together, these findings indicate that the putamen and the basal ganglia may contribute importantly to the shaping of an individual subjective sensory experience by utilizing internal cognitive information to influence activity of large areas of the cerebral cortex.

Several studies have suggested that, in higher primates, nociceptive somatosensory information is processed in parallel in the primary (S1) and secondary (S2) somatosensory cortices, whereas non-nociceptive somatosensory input is processed serially from S1 to S2. However, evidence suggesting that both nociceptive and non-nociceptive somatosensory inputs are processed in parallel in S1 and S2 also exists. Here, we aimed to clarify whether or not the hierarchical organization of nociceptive and non-nociceptive somatosensory processing in S1 and S2 differs in humans. To address this question, we applied dynamic causal modeling and Bayesian model selection to functional magnetic resonance imaging (fMRI) data collected during the selective stimulation of nociceptive and non-nociceptive somatosensory afferents in humans. This novel approach allowed us to explore how nociceptive and non-nociceptive somatosensory information flows within the somatosensory system. We found that the neural activities elicited by both nociceptive and non-nociceptive somatosensory stimuli are best explained by models in which the fMRI responses in both S1 and S2 depend on direct thalamocortical projections. These observations indicate that, in humans, both nociceptive and non-nociceptive information are processed in parallel in S1 and S2.

This commentary on ideas about neural mechanisms underlying pain is aimed at providing perspective for a reader who does not work in the field of mammalian somatic sensation. It is not a comprehensive review of the literature. The organization is historical to chronicle the evolution of ideas. The aim is to call attention to source of concepts and how various ideas have fared over time. One difficulty in relating concepts about pain is that the term is used to refer to human and animal reactions ranging from protective spinal reflexes to complex affective behaviors. As a result, the spectrum of "pain"-related neural organization extends to operation of multiple neuronal arrangements. Thinking about pain has shadowed progress in understanding biological mechanisms, in particular the manner of function of nervous systems. This essay concentrates on the evolution of information and concepts from the early 19th century to the present. Topics include the assumptions underlying currently active theories about pain mechanisms. At the end, brief consideration is given to present-day issues, e.g., chronic pain, central pain, and the view of pain as an emotion rather than a sensation. The conceptual progression shows that current controversies have old roots and that failed percepts often resurface after seemingly having been put to rest by argument and evidence., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Manganese ion (Mn(2+)) was used as a paramagnetic contrast agent in T1-weighted magnetic resonance imaging (MRI) images. They enter neural cells though voltage-gated calcium channels and are activity-dependently transported along axons and across synapses. The aim of the present study was to investigate the nociceptive medial thalamus projection in rats by activity-dependent manganese-enhanced magnetic resonance imaging (MEMRI). Rats under urethane and α-chloralose anesthesia were microinjected with manganese chloride (MnCl(2), 120mmol/L, iontophoretically with a 5-μA current for 15min) into the right medial thalamus. Innocuous (at a 50-μA intensity for 0.2ms) or noxious (at a 5-mA intensity for 2ms) electrical stimuli were applied through a pair of needles in the left forepaw pads once every 6s for 5h. Enhanced transport of Mn(2+) were found in the anterior cingulate cortex, midcingulate cortex, retrosplenial cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala in the noxious-stimulated group. Enhancements in the anterior cingulate cortex, midcingulate cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala, but not the retrosplenial cortex, were attenuated by an intraperitoneal injection of morphine (5mg/kg and 1mg/kg/h, intraperitoneal). These results indicate that a combination of MEMRI with activity-induced manganese-dependent contrast is useful for delineating functional connections in the pain pathway. Noxious stimulation induced enhancement of manganese ion transportation from medial thalamus to cingulate cortex and medial striatum, but not motor cortex. A combination of manganese-enhanced magnetic resonance imaging with activity-dependent contrast is useful for delineating functional connections of the medial pain pathway., (Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region.

Central pain with dissociated thermoalgesic sensory loss is common in spinal and brainstem syndromes but not in cortical lesions. Out of a series of 270 patients investigated because of somatosensory abnormalities, we identified five subjects presenting with central pain and pure thermoalgesic sensory loss contralateral to cortical stroke. All of the patients had involvement of the posterior insula and inner parietal operculum. Lemniscal sensory modalities (position sense, graphaestesia, stereognosis) and somatosensory evoked potentials to non-noxious inputs were always preserved, while thermal and pain sensations were profoundly altered, and laser-evoked potentials to thermo-nocoiceptive stimuli were always abnormal. Central pain resulting from posterior parasylvian lesions appears to be a distinct entity that can be identified unambiguously on the basis of clinical, radiological and electrophysiological data. It presents with predominant or isolated deficits for pain and temperature sensations, and is paradoxically closer to pain syndromes from brainstem lesions affecting selectively the spinothalamic pathways than to those caused by focal lesions of the posterior thalamus. The term 'pseudo-thalamic' is therefore inappropriate to describe it, and we propose parasylvian or operculo-insular pain as appropriate labels. Parasylvian pain may be extremely difficult to treat; the magnitude of pain-temperature sensory disturbances may be prognostic for its development, hence the importance of early sensory assessment with quantitative methods.

Thalamic intralaminar and medial nuclei participate mainly in affective and motivational aspects of pain processing. Unique to the present study were identification and characterization of spontaneously active neurons in the central lateral nucleus (CL) of the intralaminar thalamus, which were found to respond only to viscerally evoked noxious stimuli in animals under pentobarbital anesthesia. Responses to noxious colorectal distention, intrapancreatic bradykinin, intraperitoneal dilute acetic acid, and greater splanchnic nerve electrical stimulation were characterized. Electrophysiological recordings revealed activity in most CL neurons (93%) was excited (69%) or inhibited (31%) in response to noxious visceral stimulation of visceral nerves. Expression of c-Fos observed in CL nucleus after intensive visceral stimulation confirmed the activation. However, excited CL neurons did not have somatic fields, except in 3 of 43 (7%) CL neurons tested for responses to somatic stimulation (innocuous brush and noxious pinch). Intrathecal administration of morphine significantly reduced the increased responses of CL neurons to colorectal and pancreatic stimuli and was naloxone reversible. High-level thoracic midline dorsal column (DC) myelotomy also dramatically reduced responses, identifying the DC as a major route of travel from the spinal cord for CL input, in addition to input traveling ventromedially in the spinothalamic tract identified anatomically in a previous study. Spinal cord and lower brain stem cells providing input to medial thalamus were mapped after stereotaxic injections of a retrograde dye. These data combined with our previous data suggest that the CL nucleus is an important component of a medial visceral nociceptive system that may mediate attentional, affective, endocrine, motor, and autonomic responses to noxious visceral stimuli.

Neuropathic pain is a complex subject, not completely understood yet, and it is quite common in clinical practice, even outside of a neurological context. Neuropathic pain, often being a chronic process, alters and profoundly affects the quality of life. Therefore, the management of neuropathic pain involves a multidimensional approach, as physicians have to take care not only of the objective aspects of the problem, but also of the subjective experiences of pain. This explains why the attainment of a diagnosis becomes so important, as it allows clinicians to treat the patients with the best therapeutic approach. Several studies report the use of brain-evoked potentials for studying patients suffering from neuropathic pain. In particular, laser- and contact heat-evoked potentials have proved useful for the diagnosis of clinical conditions characterized by neuropathic pain. However, although these tools are reliable and safe instruments to assess function of the nociceptive system, their use is still largely confined to research purposes.

There are well-documented sex differences in the prevalence of various painful disorders. To comprehend the mechanisms underlying these differences requires an understanding of the molecular organisation and systems biology that are responsible for the pain experience. The pain system evolved to secure the survival of the animal under a variety of environmental constraints and needed to be flexible enough to compete against other behavioural needs and homeostatic demands. From the periphery to the cortex, mechanisms exist to facilitate or inhibit nociceptive signalling and it is this inherent plasticity that is thought to be perturbed in chronic pain states. There is limited evidence to suggest that polymorphisms or mutations in certain genes and gender can influence the pain experience but it seems likely that epigenetics and the influence of past experience are responsible for a substantial part of the variation between sexes and between individuals.

Injury to the spinal cord (SCI) can produce a constellation of problems including chronic pain, autonomic dysreflexia, and motor dysfunction. Neuroplasticity in the form of fiber sprouting or the lack thereof is an important phenomenon that can contribute to the deleterious effects of SCI. Aberrant sprouting of primary afferent fibers and synaptogenesis within incorrect dorsal horn laminae leads to the development and maintenance of chronic pain as well as autonomic dysreflexia. At the same time, interruption of connections between supraspinal motor control centers and spinal cord output cells, due to lack of successful regenerative sprouting of injured descending fiber tracts, contributes to motor deficits. Similarities in the molecular control of axonal growth of motor and sensory fibers have made the development of cogent therapies difficult. In this study, we discuss recent findings related to the degradation of inhibitory barriers and promotion of sprouting of motor fibers as a strategy for the restoration of motor function and note that this may induce primary afferent fiber sprouting that can contribute to chronic pain. We highlight the importance of careful attentiveness to off-target molecular- and circuit-level modulation of nociceptive processing while moving forward with the development of therapies that will restore motor function after SCI.

Bone is the most common site of chronic pain in patients with metastatic cancer. What remains unclear are the mechanisms that generate this pain and why bone cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized bone. This tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of activating transcription factor 3 (ATF3) and galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur. Similar neurochemical changes have been described following peripheral nerve injury and in other non-cancerous neuropathic pain states. Chronic treatment with gabapentin did not influence tumor growth, tumor-induced bone destruction or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked bone cancer-related pain behaviors. These results suggest that even when the tumor is confined within the bone, a component of bone cancer pain is due to tumor-induced injury to primary afferent nerve fibers that innervate the tumor-bearing bone. Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this chronic pain state.

We investigated the integrity of the ascending pathways for pain sensitivity in the early stage of type 1 diabetes mellitus, by measuring the N1 component and the conventional N2/P2 vertex potentials of laser evoked potentials (LEPs). Brain responses to laser stimuli were obtained in 21 healthy volunteers and 21 type 1 diabetic patients, without either clinical neuropathy or electrophysiological evidence of large-fiber damage. In diabetic patients N1 and P2 latencies were prolonged and the N1 and N2/P2 amplitudes were decreased after foot stimulation. A significant reduction of the conduction velocity of Adelta fibers in the lower limbs was also observed. LEPs reveal an early, subclinical and selective damage of pain sensation in diabetic patients. N1 and P2 potentials are delayed and decreased in parallel giving evidence that LEP abnormalities are not secondary to a cognitive dysfunction and mostly reflect a small-fiber dysfunction.

In this study we have tested in the rat, whether trigeminal tractotomy, which deprives the spinal trigeminal nucleus caudalis (Sp5C) of its trigeminal inputs, affected differentially nociceptive responses mediated by C- vs. Adelta-nociceptors from oral and perioral regions. Tractotomy had no effect on the threshold of the jaw opening reflex, induced by incisive pulp stimulation (Adelta-fiber-mediated), but blocked the formalin response (mainly C-fiber-mediated). These results suggest that nociceptive responses mediated by trigeminal C-fibers completely depend on the integrity of the Sp5C, while intraoral sensations triggered Adelta-fibers (especially of dental origin) are primarily processed in the rostral part of the spinal trigeminal nucleus.

Visceral pain, although different from somatic pain in several important features, is not as widely researched and consequently our knowledge of neurophysiologic mechanisms as well as clinical management of visceral pain states remains unsatisfactory. Several recent studies have employed different visceral pain animal models to provide insight into the peripheral and central nervous system mechanisms underlying pain originating from the urinary bladder, ureter, and gastrointestinal tract. The effects of opioid and nonopioid drugs in these models have also been evaluated and are reviewed in this article. The importance of anatomic pathways relaying pain sensation in the central nervous system, particularly the newly described dorsal column pathway, is also discussed. In human subjects, new techniques like positron emission tomography are now being used to better understand visceral pain perception. Such findings deriving from basic animal research and human studies summarized in the present overview lead to a better understanding of visceral pain states and may be helpful in developing better treatment strategies to combat visceral pain states in the clinical setting.

Visceral pain is of great concern to the medical community because it remains particularly resistant to current clinical treatments. A serendipitous and initially unexplainable clinical finding that a punctate midline dorsal column lesion is effective in eliminating visceral pain, however, has initiated a resurgence of interest in the study of the basic mechanisms of visceral nociception. Clinical and anatomic findings have determined that visceral pain either of thoracic or pelvic origin can be relieved by carefully placed lesions directed at the lateral edge or the medial edge of the gracile fasciculus, respectively. Studies are demonstrating that visceral pain is quite unique from cutaneous pain.

Pain, particularly chronic pain, arises from the interaction of multiple simultaneously operating physiologic processes. The current understanding of the anatomy and physiology of pain is limited to a characterization of pathways and does not explain why a particular stimulus is felt as pain of a particular kind and intensity. In this article, we trace the afferent pain pathways from periphery (reception) to center (perception), i.e., from peripheral nerve, through the spinal cord and brain stem, to the thalamus and cerebral cortex. A number of neurosurgical procedures for the treatment of pain are discussed, and their anatomic basis is explained.

Spinal cord injury (SCI) results in chronic pain states in which the underlying mechanism is poorly understood. To begin to explore possible mechanisms, calcitonin gene-related peptide (CGRP), a neuropeptide confined to fine primary afferent terminals in laminae I and II in the dorsal horn of the spinal cord and implicated in pain transmission, was selected. Immunocytochemical techniques were used to examine the temporal and spatial distribution of CGRP in the spinal cord following T-13 spinal cord hemisection in adult male Sprague-Dawley rats compared to that seen in sham controls. Spinal cords from both hemisected and sham control groups (N = 5, per time point) were examined on postoperative day (POD) 3, 5, 7, 14, and 108 following surgery. Sham operated rats displayed CGRP immunoreaction product in laminae I and II outer, Lissauer's tract, dorsal roots, and motor neurons of the ventral horn. In the hemisected group, densiometric data demonstrated an increased deposition of reaction product that was statistically significant, in laminae III and IV, both ipsilateral and contralateral to the lesion that extended at least two segments rostral and caudal to the hemisection site by POD 14, and remained significantly elevated as long as POD 108. Since upregulation alone of CGRP would occur in an acute temporal window (by 2 to 3 days following spinal injury), these results are interpreted to be invasion of laminae III and IV by sprouting of CGRP containing fine primary afferents. Intrathecal delivery of antibodies against purified 2.5S nerve growth factor for 14 days to the hemisected group resulted in CGRP density in laminae I through IV that was significantly less than that seen in untreated or vehicle treated hemisected groups and to sham controls. These data indicate changes in density and distribution of CGRP following spinal hemisection that can be manipulated by changes in endogenous levels of NGF. These observations suggest possible strategies for intervention in the development of various pain states in human SCI.

The aims of the study were to use functional magnetic resonance imaging (fMRI) to 1) locate pain-related regions in the anterior cingulate cortex (ACC) of normal human subjects and 2) determine whether each subject's pain-related activation is congruent with ACC regions involved in attention-demanding cognitive processes. Ten normal subjects underwent fMRI with a 1.5-T standard commercial MRI scanner. A conventional gradient echo technique was used to obtain data from a single 4-mm sagittal slice of the left ACC, approximately 3.5 mm from midline. For each subject, interleaved sets of 6 images were obtained during a pain task, an attention-demanding task, and at rest, for a total of 36 images per task. Pain of different intensities was evoked via electrical stimulation of the right median nerve. The attention-demanding task consisted of silent word generation (verbal fluency). Additional experiments obtained data from the right ACC. A pixel-by-pixel statistical analysis of task versus rest images was used to determine task-related activated regions. The pain task resulted in a 1.6-4.0% increase in mean signal intensity within a small region of the ACC. The exact location of this activation varied from subject to subject, but was typically in the posterior part of area 24. The signal intensity changes within this region correlated with pain intensity reported by the subject. The attention-demanding tasks increased the mean signal intensity by 1.3-3.3% in a region anterior and/or superior to the pain-related activation in each subject. The activated region was typically larger than the pain-related activation. In some cases this activation was at or superior to the ACC border, near the supplementary motor area. These regions did not show any pain-intensity-related activation. In one subject both right and left ACC were imaged, revealing bilateral ACC activation during the attention task but only contralateral pain-related activation. These findings shed light on pain- and attention-related cognitive processes. The results provide evidence for a region in the posterior part of the ACC that is involved in pain and a more anterior region involved in other attention-demanding cognitive tasks.

Pain relief was obtainable when deep brain stimulation was tried in the sensory thalamic nucleus in a patient with deaffereantation pain to cervical myelopathy. The electrode was histologically verified in post-mortem examination after 20 months and the localization of contact points of the implanted electrode was estimated. The cathode appeared to have been placed in the region from Vim to the rostral border of Vci while the anode was in the medical lemniscus region. Stimulation of the Vim nucleus might have had a pain relieving effects because no facial paraesthesiae was evoked by stimulation. The implanted electrode caused only minor histological changes.

Feedback controlled constant force stimuli of 4, 6 and 8 N intensities and of 120 s duration were applied to the receptive fields of cutaneous afferent fibers in the rat's tail. Two types of nociceptive units showed sustained discharges during these stimuli: "polymodal" unmyelinated C-units (MH-C units, N = 18, c.v. 0.5-0.9 m/s) and high-threshold mechanoreceptive A-delta-units (HTM-units, N = 10, c.v. 1.9-11.2 m/s). In addition two classes of sensitive low threshold mechanoreceptors, SA I (N = 6) and SA II (N = 5) units, responded to the prolonged mechanical stimuli. At the onset of a noxious pressure, 11 of the 18 polymodal nociceptors exhibited dynamic responses (lasting about 10 s) which were followed by slowly adapting tonic discharges that lasted for the duration of the stimuli. The remaining polymodal C-fiber units (8/18) did not show dynamic discharges at 4 and 6 N. Phasic and tonic discharges were positively correlated with stimulus strength. The HTM-units encoded stimulation intensity mainly by their dynamic discharges. The tonic discharges of these units displayed faster adaptation rates with stronger mechanical stimuli, i.e. encoding of stimulation intensity became progressively weaker during the tonic phase. The discharges of sensitive SA I and SA II units with A beta axons were not positively correlated with the strength of noxious pressure stimuli. Tonic discharge rates of SA I units were negatively correlated to stimulus strength, whereas SA II units usually stopped firing in the course of a stimulus and became reversibly irresponsive to mechanical stimulation. Possible afferent mechanisms underlying the induction of pain by sustained noxious mechanical stimulation are discussed.