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Pain Physician 2011Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical... (Review)
Review
Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross talk of neural mechanisms of pain and tolerance. Clinicians should suspect OIH when opioid treatment's effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the original pain, and increased levels of pain with increasing dosages. The treatment involves reducing the opioid dosage, tapering them off, or supplementation with NMDA receptor modulators. This comprehensive review addresses terminology and definition, prevalence, the evidence for mechanism and physiology with analysis of various factors leading to OIH, and effective strategies for preventing, reversing, or managing OIH.
Topics: Analgesics, Opioid; Chronic Disease; Humans; Hyperalgesia; Pain; Prevalence
PubMed: 21412369
DOI: No ID Found -
The Journal of Manual & Manipulative... Feb 2022Tensioning techniqueswere the first neurodynamic techniques used therapeutically in the management of people with neuropathies. This article aims to provide a balanced...
Tensioning techniqueswere the first neurodynamic techniques used therapeutically in the management of people with neuropathies. This article aims to provide a balanced evidence-informed view on the effects of optimal tensile loading on peripheral nerves and the use of tensioning techniques. Whilst the early use of neurodynamics was centered within a mechanical paradigm, research into the working mechanisms of tensioning techniques revealed neuroimmune, neurophysiological, and neurochemical effects. and research confirms that tensile loading is required for mechanical adaptation of healthy and healing neurons and nerves. Moreover, elimination of tensile load can have detrimental effects on the nervous system. Beneficial effects of tensile loading and tensioning techniques, contributing to restored homeostasis at the entrapment site, dorsal root ganglia and spinal cord, include neuronal cell differentiation, neurite outgrowth and orientation, increased endogenous opioid receptors, reduced fibrosis and intraneural scar formation, improved nerve regeneration and remyelination, increased muscle power and locomotion, less mechanical and thermal hyperalgesia and allodynia, and improved conditioned pain modulation. However, animal and cellular models also show that 'excessive' tensile forces have negative effects on the nervous system. Although robust and designed to withstand mechanical load, the nervous system is equally a delicate system. Mechanical loads that can be easily handled by a healthy nervous system, may be sufficient to aggravate clinical symptoms in patients. This paper aims to contribute to a more balanced view regarding the use of neurodynamics and more specifically tensioning techniques.
Topics: Animals; Ganglia, Spinal; Humans; Hyperalgesia; Neurons; Peripheral Nervous System Diseases; Spinal Cord
PubMed: 34781843
DOI: 10.1080/10669817.2021.2001736 -
International Journal of Molecular... Nov 2020Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two... (Review)
Review
Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD's mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD's action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD's pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD's action and future perspectives for research.
Topics: Analgesics; Cannabidiol; Cannabinoids; Dronabinol; Humans; Hyperalgesia; Neuralgia; Pain Management
PubMed: 33238607
DOI: 10.3390/ijms21228870 -
Science Translational Medicine Oct 2018The brush of a feather and a pinprick are perceived as distinct sensations because they are detected by discrete cutaneous sensory neurons. Inflammation or nerve injury...
The brush of a feather and a pinprick are perceived as distinct sensations because they are detected by discrete cutaneous sensory neurons. Inflammation or nerve injury can disrupt this sensory coding and result in maladaptive pain states, including mechanical allodynia, the development of pain in response to innocuous touch. However, the molecular mechanisms underlying the alteration of mechanical sensitization are poorly understood. In mice and humans, loss of mechanically activated PIEZO2 channels results in the inability to sense discriminative touch. However, the role of Piezo2 in acute and sensitized mechanical pain is not well defined. Here, we showed that optogenetic activation of -expressing sensory neurons induced nociception in mice. Mice lacking in caudal sensory neurons had impaired nocifensive responses to mechanical stimuli. Consistently, ex vivo recordings in skin-nerve preparations from these mice showed diminished Aδ-nociceptor and C-fiber firing in response to mechanical stimulation. Punctate and dynamic allodynia in response to capsaicin-induced inflammation and spared nerve injury was absent in Piezo2-deficient mice. These results indicate that Piezo2 mediates inflammation- and nerve injury-induced sensitized mechanical pain, and suggest that targeting PIEZO2 might be an effective strategy for treating mechanical allodynia.
Topics: Action Potentials; Animals; Behavior, Animal; Capsaicin; Hyperalgesia; Ion Channels; Mechanotransduction, Cellular; Mice, Knockout; Neurons; Nociception; Nociceptors; Pain
PubMed: 30305457
DOI: 10.1126/scitranslmed.aat9897 -
Science (New York, N.Y.) Jan 2019Pain is an unpleasant experience. How the brain's affective neural circuits attribute this aversive quality to nociceptive information remains unknown. By means of...
Pain is an unpleasant experience. How the brain's affective neural circuits attribute this aversive quality to nociceptive information remains unknown. By means of time-lapse in vivo calcium imaging and neural activity manipulation in freely behaving mice encountering noxious stimuli, we identified a distinct neural ensemble in the basolateral amygdala that encodes the negative affective valence of pain. Silencing this nociceptive ensemble alleviated pain affective-motivational behaviors without altering the detection of noxious stimuli, withdrawal reflexes, anxiety, or reward. Following peripheral nerve injury, innocuous stimuli activated this nociceptive ensemble to drive dysfunctional perceptual changes associated with neuropathic pain, including pain aversion to light touch (allodynia). These results identify the amygdalar representations of noxious stimuli that are functionally required for the negative affective qualities of acute and chronic pain perception.
Topics: Affect; Amygdala; Animals; Anxiety; Behavior, Animal; Calcium; Chronic Pain; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Motivation; Motor Activity; Neuralgia; Pain Perception
PubMed: 30655440
DOI: 10.1126/science.aap8586 -
Brain : a Journal of Neurology Feb 2023Chemotherapy-induced peripheral neuropathy is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced...
Chemotherapy-induced peripheral neuropathy is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of chemotherapy-induced peripheral neuropathy characterized by mechanical and cold hypersensitivity. Current therapies for chemotherapy-induced peripheral neuropathy are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of chemotherapy-induced peripheral neuropathy and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. Sigma-1 receptor antagonist, a highly selective antagonist of Sigma-1 receptor, has shown effectiveness in a phase II clinical trial for oxaliplatin chemotherapy-induced peripheral neuropathy. However, the mechanisms involved in the beneficial effects of Sigma-1 receptor antagonist are little understood. We combined biochemical and biophysical (i.e. intermolecular Förster resonance energy transfer) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including Sigma-1 receptor antagonist, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, Sigma-1 receptor antagonists reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a Sigma-1 receptor antagonists prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of chemotherapy-induced peripheral neuropathy and could inform the development of novel therapeutics for neuropathic pain.
Topics: Mice; Humans; Animals; Oxaliplatin; TRPA1 Cation Channel; Antineoplastic Agents; Transient Receptor Potential Channels; Neuralgia; Hyperalgesia; Sigma-1 Receptor
PubMed: 35871491
DOI: 10.1093/brain/awac273 -
Pflugers Archiv : European Journal of... Jan 2015Mechanical allodynia (other pain) is a painful sensation caused by innocuous stimuli like light touch. Unlike inflammatory hyperalgesia that has a protective role,... (Review)
Review
Mechanical allodynia (other pain) is a painful sensation caused by innocuous stimuli like light touch. Unlike inflammatory hyperalgesia that has a protective role, allodynia has no obvious biological utility. Allodynia is associated with nerve damage in conditions such as diabetes, and is likely to become an increasing clinical problem. Unfortunately, the mechanistic basis of this enhanced sensitivity is incompletely understood. In this review, we describe evidence for the involvement of candidate mechanosensitive channels such as Piezo2 and their role in allodynia, as well as the peripheral and central nervous system mechanisms that have also been implicated in this form of pain. Specific treatments that block allodynia could be very useful if the cell and molecular basis of the condition could be determined. There are many potential mechanisms underlying this condition ranging from alterations in mechanotransduction and sensory neuron excitability to the actions of inflammatory mediators and wiring changes in the CNS. As with other pain conditions, it is likely that the range of redundant mechanisms that cause allodynia will make therapeutic intervention problematic.
Topics: Animals; Humans; Hyperalgesia; Ion Channel Gating; Ion Channels; Mechanotransduction, Cellular; Models, Neurological; Nociceptors; Touch
PubMed: 24846747
DOI: 10.1007/s00424-014-1532-0 -
Journal of Neuroinflammation Jun 2022Gut microbiota has been found involved in neuronal functions and neurological disorders. Whether and how gut microbiota impacts chronic somatic pain disorders remain...
BACKGROUND
Gut microbiota has been found involved in neuronal functions and neurological disorders. Whether and how gut microbiota impacts chronic somatic pain disorders remain elusive.
METHODS
Neuropathic pain was produced by different forms of injury or diseases, the chronic constriction injury (CCI) of the sciatic nerves, oxaliplatin (OXA) chemotherapy, and streptozocin (STZ)-induced diabetes in mice. Continuous feeding of antibiotics (ABX) cocktail was used to cause major depletion of the gut microbiota. Fecal microbiota, biochemical changes in the spinal cord and dorsal root ganglion (DRG), and the behaviorally expressed painful syndromes were assessed.
RESULTS
Under condition of gut microbiota depletion, CCI, OXA, or STZ treatment-induced thermal hyperalgesia or mechanical allodynia were prevented or completely suppressed. Gut microbiota depletion also prevented CCI or STZ treatment-induced glial cell activation in the spinal cord and inhibited cytokine production in DRG in OXA model. Interestingly, STZ treatment failed to induce the diabetic high blood glucose and painful hypersensitivity in animals with the gut microbiota depletion. ABX feeding starting simultaneously with CCI, OXA, or STZ treatment resulted in instant analgesia in all the animals. ABX feeding starting after establishment of the neuropathic pain in CCI- and STZ-, but not OXA-treated animals produced significant alleviation of the thermal hyeralgesia or mechanical allodynia. Transplantation of fecal bacteria from SPF mice to ABX-treated mice partially restored the gut microbiota and fully rescued the behaviorally expressed neuropathic pain, of which, Akkermansia, Bacteroides, and Desulfovibrionaceae phylus may play a key role.
CONCLUSION
This study demonstrates distinct roles of gut microbiota in the pathogenesis of chronic painful conditions with nerve injury, chemotherapy and diabetic neuropathy and supports the clinical significance of fecal bacteria transplantation.
Topics: Animals; Anti-Bacterial Agents; Chronic Pain; Diabetes Mellitus; Gastrointestinal Microbiome; Hyperalgesia; Mice; Neuralgia; Rats; Rats, Sprague-Dawley
PubMed: 35764988
DOI: 10.1186/s12974-022-02523-w -
Physiological Reviews Apr 2009Hyperalgesia and allodynia are frequent symptoms of disease and may be useful adaptations to protect vulnerable tissues. Both may, however, also emerge as diseases in... (Review)
Review
Hyperalgesia and allodynia are frequent symptoms of disease and may be useful adaptations to protect vulnerable tissues. Both may, however, also emerge as diseases in their own right. Considerable progress has been made in developing clinically relevant animal models for identifying the most significant underlying mechanisms. This review deals with experimental models that are currently used to measure (sect. II) or to induce (sect. III) hyperalgesia and allodynia in animals. Induction and expression of hyperalgesia and allodynia are context sensitive. This is discussed in section IV. Neuronal and nonneuronal cell populations have been identified that are indispensable for the induction and/or the expression of hyperalgesia and allodynia as summarized in section V. This review focuses on highly topical spinal mechanisms of hyperalgesia and allodynia including intrinsic and synaptic plasticity, the modulation of inhibitory control (sect. VI), and neuroimmune interactions (sect. VII). The scientific use of language improves also in the field of pain research. Refined definitions of some technical terms including the new definitions of hyperalgesia and allodynia by the International Association for the Study of Pain are illustrated and annotated in section I.
Topics: Animals; Disease Models, Animal; Female; Hyperalgesia; Male; Neuronal Plasticity; Nociceptors; Rats; Spinal Nerves; Touch
PubMed: 19342617
DOI: 10.1152/physrev.00025.2008 -
Frontiers in Immunology 2022Histone lysine crotonylation (KCR), a novel epigenetic modification, is important in regulating a broad spectrum of biological processes and various diseases. However,...
Histone lysine crotonylation (KCR), a novel epigenetic modification, is important in regulating a broad spectrum of biological processes and various diseases. However, whether KCR is involved in neuropathic pain remains to be elucidated. We found KCR occurs in macrophages, sensory neurons, and satellite glial cells of trigeminal ganglia (TG), neurons, astrocytes, and microglia of the medulla oblongata. KCR in TG was detected mainly in small and medium sensory neurons, to a lesser extent in large neurons. Peripheral nerve injury elevated KCR levels in macrophages in the trigeminal and dorsal root ganglia and microglia in the medulla oblongata but reduced KCR levels in sensory neurons. Inhibition of histone crotonyltransferases (p300) by intra-TG or intrathecal administration of C646 significantly alleviated partial infraorbital nerve transection (pIONT)- or spinal nerve ligation (SNL)-induced mechanical allodynia and thermal hyperalgesia. Intra-TG or intrathecal administration of Crotonyl coenzyme A trilithium salt to upregulate KCR dose-dependently induced mechanical allodynia and thermal hyperalgesia in mice. Mechanismly, inhibition of p300 alleviated pIONT-induced macrophage activation and reduced the expression of pain-related inflammatory cytokines , and chemokines and . Correspondingly, exogenous crotonyl-CoA induced macrophage activation and the expression of , , , and in TG, which C646 can repress. These findings suggest that might be functionally involved in neuropathic pain and neuroinflammation regulation.
Topics: Animals; Histones; Hyperalgesia; Lysine; Mice; Neuralgia; Sensory Receptor Cells; Tumor Necrosis Factor-alpha
PubMed: 35911694
DOI: 10.3389/fimmu.2022.885685