Altered Interoceptive Perception and the Effects of Interoceptive Analgesia in Musculoskeletal, Primary, and Neuropathic Chronic Pain Conditions.
ABSTRACT: Chronic pain (CP) severely disrupts the daily life of millions. Interoception (i.e., sensing the physiological condition of the body) plays a pivotal role in the aetiology and maintenance of CP. As pain is inherently an interoceptive signal, interoceptive frameworks provide important, but underutilized, approaches to this condition. Here we first investigated three facets of interoceptive perception in CP, compared with pain-free controls. We then introduce a novel interoceptive treatment and demonstrate its capacity to reduce pain severity in CP, potentially providing complementary analgesic treatments. Study 1 measured interoceptive accuracy, confidence and sensibility in patients (N = 60) with primary, secondary musculoskeletal, and neuropathic CP. Compared with matched controls, CP participants exhibited significantly lower interoceptive accuracy and interoceptive confidence. Pain severity was predicted positively by interoceptive accuracy, anxiety and depression, and negatively by interoceptive confidence. Study 2 tested a promising new interoceptive treatment for CP, in a single-blind between-subjects design (N = 51) with primary, secondary musculoskeletal, and neuropathic CP patients. The treatment specifically activates the C-Tactile system, by means of controlled stimulation of interoceptive unmyelinated afferents, at 3 cm/s with a force of 2.5 mN. This treatment led to significant pain reduction (mean 23%) in the CP treatment group after only 11 min, while CP controls who received comparable but non-interoceptive stimulation reported no change in pain intensity. These studies highlight the importance of interoceptive approaches to CP and demonstrate the potential of this novel method of C-Tactile stimulation to provide complementary analgesic treatments.
Project description:Fibromyalgia is a widespread chronic pain disease characterized by generalized musculoskeletal pain and fatigue. It substantially affects patients' relationship with their bodies and quality of life, but few studies have investigated the relationship between pain and body awareness in fibromyalgia. We examined exteroceptive and interoceptive aspects of body awareness in 30 women with fibromyalgia and 29 control participants. Exteroceptive body awareness was assessed by a body-scaled action-anticipation task in which participants estimated whether they could pass through apertures of different widths. Interoceptive sensitivity (IS) was assessed by a heartbeat detection task where participants counted their heartbeats during different time intervals. Interoceptive awareness was assessed by the Multidimensional Assessment of Interoceptive Awareness (MAIA). The "passability ratio" (the aperture size for a 50% positive response rate, divided by shoulder width), assessed by the body-scaled action-anticipation task, was higher for fibromyalgia participants, indicating disrupted exteroceptive awareness. Overestimating body size correlated positively with pain and its impact on functionality, but not with pain intensity. There was no difference in IS between groups. Fibromyalgia patients exhibited a higher tendency to note bodily sensations and decreased body confidence. In addition, the passability ratio and IS score correlated negatively across the whole sample, suggesting an inverse relationship between exteroceptive and interoceptive body awareness. There was a lower tendency to actively listen to the body for insight, with higher passability ratios across the whole sample. Based on our results and building on the fear-avoidance model, we outline a proposal that highlights possible interactions between exteroceptive and interoceptive body awareness and pain. Movement based contemplative practices that target sensory-motor integration and foster non-judgmental reconnection with bodily sensations are suggested to improve body confidence, functionality, and quality of life.
Project description:BACKGROUND: Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain. RESULTS: Antidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 microM and 1.87 microM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine. CONCLUSION: These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X4 receptors.
Project description:The processing and perception of individual internal bodily signals (interoception) has been differentiated to comprise different levels and processes involved. The so-called heartbeat-evoked potential (HEP) offers an additional possibility to examine automatic processing of cardiac signals. Knowledge on neural structures potentially supporting different facets of interoception is still sparse. One way to get insights into neuroanatomical function is to manipulate the activity of different brain structures. In this study, we used repetitive transcranial magnetic stimulation (rTMS) and a continuous theta-burst protocol to inhibit specific central locations of the interoceptive network including the right anterior insula and the right somatosensory cortices and assessed effects on interoceptive facets and the HEP in 18 male participants. Main results were that inhibiting anterior insula resulted in a significant decline in cardiac and respiratory interoceptive accuracy (IAc) and in a consistent decrease in perception confidence. Continuous theta-burst stimulation (cTBS) over somatosensory cortices reduced only cardiac IAc and affected perception confidence. Inhibiting right anterior insula and right somatosensory cortices increased interoceptive sensibility and reduced the HEP amplitude over frontocentral locations. Our findings strongly suggest that cTBS is an effective tool to investigate the neural network supporting interoceptive processes.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'.
Project description:Growing evidence suggests that oxidative stress, as associated with spinal cord injury (SCI), may play a critical role in both neuroinflammation and neuropathic pain conditions. The production of the endogenous aldehyde acrolein, following lipid peroxidation during the inflammatory response, may contribute to peripheral sensitization and hyperreflexia following SCI via the TRPA1-dependent mechanism. Here, we report that there are enhanced levels of acrolein and increased neuronal sensitivity to the aldehyde for at least 14 days after SCI. Concurrent with injury-induced increases in acrolein concentration is an increased expression of TRPA1 in the lumbar (L3-L6) sensory ganglia. As proof of the potential pronociceptive role for acrolein, intrathecal injections of acrolein revealed enhanced sensitivity to both tactile and thermal stimuli for up to 10 days, supporting the compound's pro-nociceptive functionality. Treatment of SCI animals with the acrolein scavenger hydralazine produced moderate improvement in tactile responses as well as robust changes in thermal sensitivity for up to 49 days. Taken together, these data suggest that acrolein directly modulates SCI-associated pain behavior, making it a novel therapeutic target for preclinical and clinical SCI as an analgesic. Following spinal cord injury (SCI), acrolein involvement in neuropathic pain is likely through direct activation and elevated levels of pro-nociceptive channel TRPA1. While acrolein elevation correlates with neuropathic pain, suppression of this aldehyde by hydralazine leads to an analgesic effect. Acrolein may serve as a novel therapeutic target for preclinical and clinical SCI to relieve both acute and chronic post-SCI neuropathic pain.
Project description:The analgesic effects of leukocyte-derived opioids have been exclusively demonstrated for somatic inflammatory pain, for example, the pain associated with surgery and arthritis. Neuropathic pain results from injury to nerves, is often resistant to current treatments, and can seriously impair a patient's quality of life. Although it has been recognized that neuronal damage can involve inflammation, it is generally assumed that immune cells act predominately as generators of neuropathic pain. However, in this study we have demonstrated that leukocytes containing opioids are essential regulators of pain in a mouse model of neuropathy. About 30%-40% of immune cells that accumulated at injured nerves expressed opioid peptides such as beta-endorphin, Met-enkephalin, and dynorphin A. Selective stimulation of these cells by local application of corticotropin-releasing factor led to opioid peptide-mediated activation of opioid receptors in damaged nerves. This ultimately abolished tactile allodynia, a highly debilitating heightened response to normally innocuous mechanical stimuli, which is symptomatic of neuropathy. Our findings suggest that selective targeting of opioid-containing immune cells promotes endogenous pain control and offers novel opportunities for management of painful neuropathies.
Project description:Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia and this temporal divergence was associated with major differences in global gene expression in dorsal root ganglia (DRG). Transcripts whose expression correlate with the onset of cold allodynia were nociceptor-related, whereas those correlating with tactile hypersensitivity were enriched for immune cell activity. Selective ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity. Whereas, depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain is contributed to by reactive processes of sensory neurons and immune cells, each leading to distinct forms of pain hypersensitivity, potentially allowing effective drug development targeted to each pain modality. Overall design: High temporal analysis of global gene expression in the DRG following spared nerve injury (SNI) correlated with behavior taken at the same time points. Expression and behavioral sensitivity taken at least daily over the first 10 days post SNI.
Project description:Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia and this temporal divergence was associated with major differences in global gene expression in dorsal root ganglia. Transcripts whose expression correlate with the onset of cold allodynia were nociceptor-related whereas those correlating with tactile hypersensitivity were enriched for immune cell activity. Selective ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity. Whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain is contributed to by reactive processes of sensory neurons and immune cells, each leading to distinct forms of pain hypersensitivity, potentially allowing effective drug development targeted to each pain modality. Overall design: High temporal analysis of global gene expression in the DRG following spared nerve injury (SNI) correlated with behavior taken at the same time points. Expression and behavioral sensitivity taken at least daily over the first 10 days post SNI.
Project description:Building on recent psychological research showing that power increases self-focused attention, we propose that having power increases accuracy in perception of bodily signals, a phenomenon known as interoceptive accuracy. Consistent with our proposition, participants in a high-power experimental condition outperformed those in the control and low-power conditions in the Schandry heartbeat-detection task. We demonstrate that the effect of power on interoceptive accuracy is not explained by participants' physiological arousal, affective state, or general intention for accuracy. Rather, consistent with our reasoning that experiencing power shifts attentional resources inward, we show that the effect of power on interoceptive accuracy is dependent on individuals' chronic tendency to focus on their internal sensations. Moreover, we demonstrate that individuals' chronic sense of power also predicts interoceptive accuracy similar to, and independent of, how their situationally induced feeling of power does. We therefore provide further support on the relation between power and enhanced perception of bodily signals. Our findings offer a novel perspective-a psychophysiological account-on how power might affect judgments and behavior. We highlight and discuss some of these intriguing possibilities for future research.
Project description:The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid efficacy in neuropathic pain, novel compounds containing opioid agonist and neurokinin 1 (NK1) receptor antagonist pharmacophores were designed. Structure-activity studies were performed on opioid agonist/NK1 receptor antagonist hybrid peptides by modification of the C-terminal amide substituents. All compounds were evaluated for their affinity and in vitro activity at the mu opioid (MOP) and delta opioid (DOP) receptors, and for their affinity and antagonist activity at the NK1 receptor. On the basis of their in vitro profiles, the analgesic properties of two new bifunctional hybrids were evaluated in naive and CCI-mice, representing models for acute and neuropathic pain, respectively. The compounds were administered to the spinal cord by lumbar puncture. In naive mice, the single pharmacophore opioid parent compounds provided better analgesic results, as compared to the hybrids (max 70% MPE), raising the acute pain threshold close to 100% MPE. On the other hand, the opioid parents gave poor analgesic effects under neuropathic pain conditions, while the best hybrid delivered robust (close to 100% MPE) and long lasting alleviation of both tactile and thermal hypersensitivity. The results presented emphasize the potential of opioid/NK1 hybrids in view of analgesia under nerve injury conditions.
Project description:Analyse of gene expression modification after chronic analgesic treatment. The hypothesis tested in the present study was that oxycodone and morphine induced gene expression modification. Results provide important information to understand the analgesic effects of oxycodone as compared to morphine in a neuropathic pain model Total RNA obtained from DRG of neuropathic or control animals after oxycodone or morphine treatment