Electrophysiological Measurements and Analysis of Nociception in Human Infants

Pain is an unpleasant sensory and emotional experience. Since infants cannot verbally report their experiences, current methods of pain assessment are based on behavioural and physiological body reactions, such as crying, body movements or changes in facial expression. While these measures demonstrate that infants mount a response following noxious stimulation, they are limited: they are based on activation of subcortical somatic and autonomic motor pathways that may not be reliably linked to central sensory processing in the brain. Knowledge of how the central nervous system responds to noxious events could provide an insight to how nociceptive information and pain is processed in newborns.The heel lancing procedure used to extract blood from hospitalised infants offers a unique opportunity to study pain in infancy. In this video we describe how electroencephalography (EEG) and electromyography (EMG) time-locked to this procedure can be used to investigate nociceptive activity in the brain and spinal cord.This integrative approach to the measurement of infant pain has the potential to pave the way for an effective and sensitive clinical measurement tool.     

Distinct Brain Systems Mediate the Effects of Nociceptive Input and Self-Regulation on Pain

Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI) imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS), an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system.     

The cerebral signature for pain perception and its modulation

Our understanding of the neural correlates of pain perception in humans has increased significantly since the advent of neuroimaging. Relating neural activity changes to the varied pain experiences has led to an increased awareness of how factors (e.g., cognition, emotion, context, injury) can separately influence pain perception. Tying this body of knowledge in humans to work in animal models of pain provides an opportunity to determine common features that reliably contribute to pain perception and its modulation. One key system that underpins the ability to change pain intensity is the brainstem's descending modulatory network with its pro- and antinociceptive components. We discuss not only the latest data describing the cerebral signature of pain and its modulation in humans, but also suggest that the brainstem plays a pivotal role in gating the degree of nociceptive transmission so that the resultant pain experienced is appropriate for the particular situation of the individual.     

Altered ATP release and metabolism in dorsal root ganglia of neuropathic rats

Recent advances in pain research provide a clear picture for the molecular mechanisms of acute pain; substantial information concerning plasticity that occurs during neuropathic pain has also become available. The peripheral mechanisms responsible for neuropathic pain are found in the altered gene/protein expression of primary sensory neurons. With damage to peripheral sensory fibers, a variety of changes in pain-related gene expression take place in dorsal root ganglion neurons. These changes, or plasticity, might underlie unique neuropathic pain-specific phenotype modifications – decreased unmyelinated-fiber functions, but increased myelinated A-fiber functions. Another characteristic change is observed in allodynia, the functional change of tactile to nociceptive perception. Throughout a series of studies, using novel nociceptive tests to characterize sensory-fiber or pain modality-specific nociceptive behaviors, it was demonstrated that communication between innocuous and noxious sensory fibers might play a role in allodynia mechanisms. Because neuropathic pain in peripheral and central demyelinating diseases develops as a result of aberrant myelination in experimental animals, demyelination seems to be a key mechanism of plasticity in neuropathic pain. More recently, we discovered that lysophosphatidic acid receptor activation initiates neuropathic pain, as well as possible peripheral mechanims of demyelination after nerve injury. These results lead to further hypotheses of physical communication between innocuous Aβ- and noxious C- or Aδ-fibers to influence the molecular mechanisms of allodynia.     

Psychophysics of sweet and fat perception in obesity: problems, solutions and new perspectives

Psychophysical comparisons seem to show that obese individuals experience normal sweet and fat sensations, they like sweetness the same or less, but like fat more than the non-obese do. These psychophysical comparisons have been made using scales (visual analogue or category) that assume intensity labels (e.g. extremely) which denote the same absolute perceived intensity to all. In reality, the perceived intensities denoted by labels vary because they depend on experiences with the substances to be judged. This variation makes comparisons invalid. Valid comparisons can be made by asking the subjects to rate their sensory/hedonic experiences in contexts that are not related to the specific experiences of interest. Using this methodology, we present the evidence that the sensory and hedonic properties of sweet and fat vary with body mass index. The obese live in different orosensory and orohedonic worlds than do the non-obese; the obese experience reduced sweetness, which probably intensifies fat sensations, and the obese like both sweet and fat more than the non-obese do. Genetic variation as well as taste pathology contribute to these results. These psychophysical advances will impact experimental as well as clinical studies of obesity and other eating disorders.     

Altered Formalin-Induced Pain and Fos Induction in the Periaqueductal Grey of Preadolescent Rats following Neonatal LPS Exposure

Animal and human studies have demonstrated that early pain experiences can produce alterations in the nociceptive systems later in life including increased sensitivity to mechanical, thermal, and chemical stimuli. However, less is known about the impact of neonatal immune challenge on future responses to noxious stimuli and the reactivity of neural substrates involved in analgesia. Here we demonstrate that rats exposed to Lipopolysaccharide (LPS; 0.05 mg/kg IP, Salmonella enteritidis) during postnatal day (PND) 3 and 5 displayed enhanced formalin-induced flinching but not licking following formalin injection at PND 22. This LPS-induced hyperalgesia was accompanied by distinct recruitment of supra-spinal regions involved in analgesia as indicated by significantly attenuated Fos-protein induction in the rostral dorsal periaqueductal grey (DPAG) as well as rostral and caudal axes of the ventrolateral PAG (VLPAG). Formalin injections were associated with increased Fos-protein labelling in lateral habenula (LHb) as compared to medial habenula (MHb), however the intensity of this labelling did not differ as a result of neonatal immune challenge. These data highlight the importance of neonatal immune priming in programming inflammatory pain sensitivity later in development and highlight the PAG as a possible mediator of this process.     

Sex differences in nociceptive withdrawal reflex and pain perception

Experimentally induced pain often reveals sex differences, with higher pain sensitivity in females. The degree of differences has been shown to depend on the stimulation and assessment methods. Since sex differences in pain develop anywhere along the physiological and psychological components of the nociceptive system, we intended to compare the nociceptive flexion reflex (NFR) as a more physiological (spinal) aspect of pain procession to the verbal pain report of intensity and unpleasantness as the more psychological (cortical) aspect. Twenty female and twenty male healthy university students were investigated by use of nociceptive flexion reflex threshold (staircase method) after electrical stimulation of the N. suralis. Furthermore, we assessed supra-threshold reflex responses (latency, amplitude and area) by applying 10 stimuli 5 mA above reflex threshold. Following each stimulation, the subjects provided pain ratings of intensity and unpleasantness on a visual analogue scale. Females exhibited marked lower nociceptive flexion reflex thresholds than males, while the supra-threshold reflex response tailored to the individual reflex threshold did not show any significant differences. The verbal pain ratings, corrected for NFR threshold, were not found to differ significantly. The large sex differences in nociception that were present in NFR threshold but not in the pain ratings corroborate the hypothesis that spinal processes contribute substantially to sex differences in pain procession.     

Pain perception, aversion and fear in fish

There is now compelling evidence that teleost fish possess similar nociceptive processing systems to those found in terrestrial vertebrates. Noxious stimulation of these nociceptors--specialised pain receptors -in the skin around the snout of fish generates neural activity that can be electrophysiologically recorded, and induces a number of behavioural and physiological changes. To determine whether changes in behaviour are more than simple responses to the noxious stimulation it is necessary to demonstrate that higher order cognitive processes such as mental state or 'affective state' are involved. However, quantifying the 'motivational affected state' of an animal--a concept encompassing not just pain but also fear, hunger, thirst and pleasure - is difficult owing to its subjectivity. Recent empirical work is beginning to test these concepts in fish, and we review a number of these studies and suggest how these general methodologies could be used to further our understanding of fish cognition and the capacity for fish to experience mental states such as fear or suffering.     

Involvement of Nitric Oxide in the Nociceptive Behavioral Reaction in Mice with Tonic Pain

In experiments on mongrel albino male mice with a nidus of tonic pain created by subcutaneous injection of 5% formalin solution into the hindlimb, we estimated changes in nociceptive behavioral reaction (licking the pain nidus) elicited by i.p. injections of compounds modulating the system of nitric oxide (NO): a blocker of NO synthase, N-nitro-L-arginine (L-NAME), and activator of NO synthesis, L-arginine (L-Arg), as well as NO donors: sodium nitroprusside (SNP) and sodium nitrate (SN). After injections of L-NAME, L-Arg, and SN, the intensity of the nociceptive behavioral reaction dropped by 55-21%, as compared with the control. In contrast, SN significantly increased the intensity of this reaction. Mechanisms responsible for modulation of the nociceptive behavioral reaction with the involvement of NO and specific features of the effects of different NO donors on this reaction (related to a complex nature of these effects) are discussed.     

Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity

Chronic pain is a debilitating condition with unknown mechanism. Nociceptive sensitivity may be regulated by genetic factors, some of which have been separately linked to neuronal progenitor cells and neuronal differentiation. This suggests that genetic factors that interfere with neuronal differentiation may contribute to a chronic increase in nociceptive sensitivity, by extending the immature, hyperexcitable stage of spinal cord neurons. Although adult rodent spinal cord neurogenesis was previously demonstrated, the fate of these progenitor cells is unknown. Here, we show that peripheral nerve injury in adult rats induces extensive spinal cord neurogenesis and a long‐term increase in the number of spinal cord laminae I–II neurons ipsilateral to injury. The production and maturation of these new neurons correlates with the time course and modulation of nociceptive behaviour, and transiently mimics the cellular and behavioural conditions present in genetically modified animal models of chronic pain. This suggests that the number of immature neurons present at any time in the spinal cord dorsal horns contributes to the regulation of nociceptive sensitivity. The continuous turnover of these neurons, which can fluctuate between normal and injured states, is a dynamic regulator of nociceptive sensitivity. In support of this hypothesis, we find that promoters of neuronal differentiation inhibit, while promoters of neurogenesis increase long‐term nociception. TrkB agonists, well‐known promoters of nociception in the short‐term, significantly inhibit long‐term nociception by promoting the differentiation of newly produced immature neurons. These findings suggest that promoters of neuronal differentiation may be used to alleviate chronic pain.     

Barcoding human physical activity to assess chronic pain conditions

Background

Modern theories define chronic pain as a multidimensional experience – the result of complex interplay between physiological and psychological factors with significant impact on patients'' physical, emotional and social functioning. The development of reliable assessment tools capable of capturing the multidimensional impact of chronic pain has challenged the medical community for decades. A number of validated tools are currently used in clinical practice however they all rely on self-reporting and are therefore inherently subjective. In this study we show that a comprehensive analysis of physical activity (PA) under real life conditions may capture behavioral aspects that may reflect physical and emotional functioning.

Methodology

PA was monitored during five consecutive days in 60 chronic pain patients and 15 pain-free healthy subjects. To analyze the various aspects of pain-related activity behaviors we defined the concept of PA ‘barcoding’. The main idea was to combine different features of PA (type, intensity, duration) to define various PA states. The temporal sequence of different states was visualized as a ‘barcode’ which indicated that significant information about daily activity can be contained in the amount and variety of PA states, and in the temporal structure of sequence. This information was quantified using complementary measures such as structural complexity metrics (information and sample entropy, Lempel-Ziv complexity), time spent in PA states, and two composite scores, which integrate all measures. The reliability of these measures to characterize chronic pain conditions was assessed by comparing groups of subjects with clinically different pain intensity.

Conclusion

The defined measures of PA showed good discriminative features. The results suggest that significant information about pain-related functional limitations is captured by the structural complexity of PA barcodes, which decreases when the intensity of pain increases. We conclude that a comprehensive analysis of daily-life PA can provide an objective appraisal of the intensity of pain.     

Galanin receptors possibly modulate the obesity-induced change in pain threshold

Pain threshold may be up-regulated or down-regulated according to gender, age, race/ethnic and psychological state. Previous studies indicated that obesity may change pain threshold, both nociceptive and antinociceptive, which resulted from obesity-reduced variation of neuroendocrine. However there is a limited understanding of its molecular mechanism underlying this variation. A lot of evidence supports that galanin increases food intake and body weight to induce obesity in animals. This peptide may also modulate nociceptive susceptibility via central galanin receptor 1 and peripheral galanin receptor 2 in dorsal root ganglion. Whereas injury and obesity may up-regulate the galanin expression and stimulate its secretion to elevate the plasma levels of subjects. Pain may increase the risk of obesity through reduced physical activity. In this review, we highlighted the multiple bilateral interrelation between obesity and pain sensitivity, between galanin and obesity and between galanin and injure-induced pain. In view of the above, we reasoned that galanin receptors possibly participated in the modulation of the obesity-induced change in pain threshold, which need further direct evidence to support as yet. This review is helpful to explore the mechanism that galanin receptors regulate the obesity-induced change of pain sensitivity and to contribute to our understanding of the relation among galanin, obesity and pain threshold.     

Post-Amputation Pain Is Associated with the Recall of an Impaired Body Representation in Dreams—Results from a Nation-Wide Survey on Limb Amputees

The experience of post-amputation pain such as phantom limb pain (PLP) and residual limb pain (RLP), is a common consequence of limb amputation, and its presence has negative effects on a person’s well-being. The continuity hypothesis of dreams suggests that the presence of such aversive experiences in the waking state should be reflected in dream content, with the recalled body representation reflecting a cognitive proxy of negative impact. In the present study, we epidemiologically assessed the presence of post-amputation pain and other amputation-related information as well as recalled body representation in dreams in a sample of 3,234 unilateral limb amputees. Data on the site and time of amputation, residual limb length, prosthesis use, lifetime prevalence of mental disorders, presence of post-amputation pain, and presence of non-painful phantom phenomena were included in logistic regression analyses using recalled body representation in dreams (impaired, intact, no memory) as dependent variable. The effects of age, sex, and frequency of dream recall were controlled for. About 22% of the subjects indicated that they were not able to remember their body representation in dreams, another 24% of the amputees recalled themselves as always intact, and only a minority of less than 3% recalled themselves as always impaired. Almost 35% of the amputees dreamed of themselves in a mixed fashion. We found that lower-limb amputation as well as the presence of PLP and RLP was positively associated with the recall of an impaired body representation in dreams. The presence of non-painful phantom phenomena, however, had no influence. These results complement previous findings and indicate complex interactions of physical body appearance and mental body representation, probably modulated by distress in the waking state. The findings are discussed against the background of alterations in cognitive processes after amputation and hypotheses suggesting an innate body model.     

Modulation of the human nociceptive reflex by cyclic movements

During static conditions the nociceptive reflex is known to vary as a function of, for example, the stimulus position, stimulus intensity, and muscle contraction. The aim of the present human study was to investigate whether the reflex and the corresponding perception of pain are modulated by cyclic movements of the limb involved. Reflexes, evoked by nociceptive electric stimulation of the sural nerve, were recorded from the biceps femoris and the rectus femoris muscles in eight volunteers. Four different experiments were performed to compare the nociceptive reflex and pain score elicited during active isometric/dynamic flexion/extension of the knee joint. The amplitudes of the reflexes were largest for the dynamic conditions. The reflexes, evoked during dynamic extension and isometric contraction of the rectus femoris muscle, had the shortest latencies but the recordings from the biceps femoris muscle were larger than from the rectus femoris muscle. Knee joint angle recordings showed that the largest angle variations occurred for the dynamic conditions and were only marginally disturbed for the isometric conditions. A given stimulus intensity evoked the highest pain intensity during isometric contractions. This indicates that there would seem to be no causal relationship between the size of the nociceptive reflex and the pain intensity.     

Gamma oscillations in human primary somatosensory cortex reflect pain perception

Successful behavior requires selection and preferred processing of relevant sensory information. The cortical representation of relevant sensory information has been related to neuronal oscillations in the gamma frequency band. Pain is of invariably high behavioral relevance and, thus, nociceptive stimuli receive preferred processing. Here, by using magnetoencephalography, we show that selective nociceptive stimuli induce gamma oscillations between 60 and 95 Hz in primary somatosensory cortex. Amplitudes of pain-induced gamma oscillations vary with objective stimulus intensity and subjective pain intensity. However, around pain threshold, perceived stimuli yielded stronger gamma oscillations than unperceived stimuli of equal stimulus intensity. These results show that pain induces gamma oscillations in primary somatosensory cortex that are particularly related to the subjective perception of pain. Our findings support the hypothesis that gamma oscillations are related to the internal representation of behaviorally relevant stimuli that should receive preferred processing.     

Languages of labor: negotiating the "real" and the relational in Indo-Fijian women's expressions of physical pain

Medical personnel in public clinics in Fiji routinely contend that state-funded medical resources are misallocated on patients who complain of, but do not actually experience, physical pain. Frequently, these patients are identified as being Indo-Fijian women (i.e., women of South Asian origin in Fiji). In this article, I examine clinical interactions between medical staff and female Indo-Fijian patients to demonstrate how "real" and 'unreal' pain are distinguished in the clinical setting and to indicate some of the roles clinical encounters play in community processes that ascribe alternative meanings to physical pain. Focusing on how both physicians and women patients foster certain interpretations of physical pain over others, I argue that the category of 'unreal' pain, as employed by Fiji's physicians, consists of pain that medical professionals consider to be induced by psychological or physical, work-related stresses. I then show how Indo-Fijian women engage in a complementary but distinct discourse that emphasizes links between physical labor and pain and suggests that, in some cases, expressions of physical pain are as much an idiom of pride as an idiom of distress.     

Mechanisms of ATP release in pain: role of pannexin and connexin channels

Pain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.     

Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCgamma). Selective inhibition of PKCgamma as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCgamma-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCgamma might provide a new tool for alleviating allodynia in the clinical setting.