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The Neuroscientist : a Review Journal... Apr 2016The ability of the body to perceive noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors. The molecular receptors of noxious... (Review)
Review
The ability of the body to perceive noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors. The molecular receptors of noxious mechanical, temperature, or chemical stimuli are expressed in these neurons and have drawn considerable attention as possible targets for analgesic development to improve treatment for the millions who suffer from chronic pain conditions. A number of thermoTRPs, a subset of the transient receptor potential family of ion channels, are activated by a wide range on noxious stimuli. In this review, we review the function of these channels and examine the evidence that thermoTRPs play a vital role in acute, inflammatory and neuropathic nociception.
Topics: Animals; Humans; Hyperalgesia; Models, Molecular; Nociceptors; Pain; Physical Stimulation; Transient Receptor Potential Channels
PubMed: 25608689
DOI: 10.1177/1073858414567884 -
Journal of Traditional Chinese Medicine... Oct 2023To evaluate the effect of berberine on morphine analgesia, tolerance, and hyperalgesia.
OBJECTIVE
To evaluate the effect of berberine on morphine analgesia, tolerance, and hyperalgesia.
METHODS
Morphine-induced acute tolerance model: mice received intraperitoneal berberine at doses of 2.5, 5.0, and 10 mg/kg; 30 min later, subcutaneous morphine 10 mg/kg was injected every hour for nine continuous h. Morphine 10 mg/kg alone was administered at 24 and 48 h. Morphine-induced chronic tolerance model: mice received intraperitoneal berberine 2.5, 5.0, and 10 mg/kg; 30 min later, 10 mg/kg morphine was injected subcutaneously for eight consecutive days. On the ninth day, morphine 10 mg/kg was given alone. Morphine-induced established tolerance model: mice were injected subcutaneously with morphine 10 mg/kg once a day for eight consecutive days. Berberine 2.5 mg/kg was administered on day one, four, and seven and morphine 10 mg/kg alone on day nine. The baseline latency (T0) and post-treatment latency (T1) were determined by the hot plate test, and the maximum possible analgesic effect (MPAE) was calculated. Nitric oxide synthase (NOS) activity and nitric oxide (NO) content in the spinal cord were measured by spectrophotometer. Verification of berberine analgesic effect by blocking N-methyl-D-aspartate (NMDA) receptor: HT-22 and HEK-293 cells transfected with NMDA plasmid were randomly divided into five groups: control group, NMDA group, berberine low-dose, medium-dose, and high-dose groups (5, 10, 20 μmol/L, respectively). Except for the control group, cells were treated with NMDA (HT-22 cells: 20 mmol/L; HEK-293 cells: 50 μmol/L). After 24 h, cell viability was detected by cell counting kit-8. The molecular mechanism between berberine and the NMDA receptor was studied by molecular docking.
RESULTS
Berberine 2.5 and 5.0 mg/kg could prolong the analgesic time of morphine. In acute and chronic morphine tolerance models, berberine could inhibit the decrease of MPAE and baseline latency (0.05). In the established tolerance model, berberine could rapidly reverse the decreased MPAE (0.05). The combination of berberine and morphine on day one could effectively inhibit the morphine-induced increase of NOS activity and NO content in the spinal cord (0.05). Berberine significantly increased the cell viability of NMDA-induced nerve injury in HT-22 and HEK-293 cells (0.05). Molecular docking showed that berberine binds to the receptor pocket of NMDA.
CONCLUSIONS
Berberine could effectively enhance and prolong the duration of morphine analgesia and inhibit the development of morphine-induced tolerance and hyperalgesia. Furthermore, berberine has a certain neuroprotective effect, which may be related to the inhibition of NMDA activity.
Topics: Humans; Animals; Mice; Hyperalgesia; Morphine; Berberine; HEK293 Cells; Molecular Docking Simulation; N-Methylaspartate; Nitric Oxide
PubMed: 37679979
DOI: 10.19852/j.cnki.jtcm.20230802.006 -
Current Osteoporosis Reports Dec 2018The goal of this review is to provide a broad overview of the current understanding of mechanisms underlying bone and joint pain. (Review)
Review
PURPOSE OF REVIEW
The goal of this review is to provide a broad overview of the current understanding of mechanisms underlying bone and joint pain.
RECENT FINDINGS
Bone or joint pathology is generally accompanied by local release of pro-inflammatory cytokines, growth factors, and neurotransmitters that activate and sensitize sensory nerves resulting in an amplified pain signal. Modulation of the pain signal within the spinal cord and brain that result in net increased facilitation is proposed to contribute to the development of chronic pain. Great strides have been made in our understanding of mechanisms underlying bone and joint pain that will guide development of improved therapeutic options for these patients. Continued research is required for improved understanding of mechanistic differences driving different components of bone and/or joint pain such as movement related pain compared to persistent background pain. Advances will guide development of more individualized and comprehensive therapeutic options.
Topics: Arthralgia; Bone and Bones; Humans; Hyperalgesia; Joints; Nociception; Pain Measurement
PubMed: 30370434
DOI: 10.1007/s11914-018-0493-1 -
Neuropsychopharmacology : Official... Jan 2022Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic tolerance and paradoxical hyperalgesia, either of which leads to increased...
Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic tolerance and paradoxical hyperalgesia, either of which leads to increased pain. Clinically, however, the relationship between these two phenomena remains elusive. By evaluating changes in mechanical nociceptive threshold in male rats, we found that in contrast to a purely analgesic control response to a single subcutaneous administration of fentanyl (25 μg/kg), in rats subjected to inflammatory pain 2 weeks previously (Day), the same test dose (D) induced a bi-phasic response: initial decreased analgesia (tolerance) followed by hyperalgesia lasting several hours. Both the tolerance and hyperalgesia were further enhanced in rats that had additionally received fentanyl on D. The dose-response profiles (5 fg to 50 μg/kg) of pain- and opioid-experienced rats were very different from pain/drug-naive rats. At ultra-low fentanyl doses (<5 ng/kg and <500 ng/kg for naïve control and pain/drug-experienced rats, respectively), solely hyperalgesia was observed in all cases. At higher doses, which now produced analgesia alone in naive rats, reduced analgesia (tolerance) coupled with hyperalgesia occurred in pain/fentanyl-experienced rats, with both phases increasing with dose. Transcriptomic and pharmacological data revealed that an overactivation of the spinal N-methyl--aspartate receptor-inducible NO synthase cascade plays a critical role in both acute tolerance and hyperalgesia, and together with the finding that the magnitudes of analgesia and associated hyperalgesia are negatively correlated, is indicative of closely related phenomena. Finally, a polyamine deficient diet prevented inducible NO synthase transcript upregulation, restored fentanyl's analgesic efficacy and suppressed the emergence of hyperalgesia.
Topics: Analgesics; Analgesics, Opioid; Animals; Diet; Fentanyl; Hyperalgesia; Male; Polyamines; Rats; Rats, Sprague-Dawley
PubMed: 34621016
DOI: 10.1038/s41386-021-01200-5 -
Arthritis Research & Therapy 2014Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that... (Review)
Review
Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-17 are also mediators of pain by directly acting on the nociceptive system. Proportions of nociceptive sensory neurons express receptors for these cytokines, and the application of cytokines rapidly changes the excitability, ion currents and second messenger systems of these neurons. By inducing persistent sensitization of nociceptive sensory neurons (C- and a proportion of Aδ-fibers) for mechanical stimuli in the joint (a process called peripheral sensitization), these cytokines significantly contribute to the persistent hyperalgesia typical for many disease states of the joint. In addition, the disease-associated release of cytokines in the spinal cord supports the generation of central sensitization. The therapeutic neutralization of proinflammatory cytokines thus not only reduces the process of inflammation but may directly reduce hyperalgesia and pain by reversing the neuronal effects of cytokines. It is emerging that different cytokines have different actions on neurons. The neutralization of tumor necrosis factor-alpha reduces both mechanical and thermal hyperalgesia of the joint. The neutralization of interleukin-1 beta attenuates thermal hyperalgesia whereas the neutralization of interleukin-6 and interleukin-17 mainly reduces mechanical hyperalgesia. These different effects are partly explained by influencing different target molecules in sensory neurons. For example, in cultured sensory neurons tumor necrosis factor-alpha and interleukin-1 beta upregulate the TRPV1 ion channel, which is involved in the transduction of heat stimuli, consistent with an effect of these cytokines in thermal hyperalgesia. By contrast, interleukin-17 upregulates the TRPV4 ion channel, which has a role in the transduction of mechanical stimuli. Thus, the analgesic potential of neutralizing cytokines seems to depend on which cytokine is mainly involved in the particular pain state.
Topics: Analgesics; Animals; Arthritis; Cytokines; Humans; Hyperalgesia; Models, Biological; Nociceptors; Pain; Sensory Receptor Cells
PubMed: 25606597
DOI: 10.1186/s13075-014-0470-8 -
Anesthesiology Feb 2016
Review
Topics: Analgesics, Opioid; Drug Tolerance; Humans; Hyperalgesia
PubMed: 26594912
DOI: 10.1097/ALN.0000000000000963 -
Memorias Do Instituto Oswaldo Cruz Mar 2005Recent advances in basic science pointed to a role for proteinases, through the activation of proteinase-activated receptors (PARs) in nociceptive mechanisms. Activation... (Review)
Review
Recent advances in basic science pointed to a role for proteinases, through the activation of proteinase-activated receptors (PARs) in nociceptive mechanisms. Activation of PAR1, PAR2 and PAR4 either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Sub-inflammatory doses of PAR2 agonist still induced hyperalgesia and allodynia while PAR2 has been shown to be implicated in the generation of hyperalgesia in different inflammatory models. In contrast, sub-inflammatory doses of PAR1 increases nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as an analgesic agent. PARs are present and functional on sensory neurons, where they participate either directly or indirectly to the transmission and/or inhibition of nociceptive messages. Taken together, the results discussed in this review highlight proteinases as signaling molecules to sensory nerves. We need to consider proteinases and the receptors that are activated by proteinases as important potential targets for the development of analgesic drugs in the treatment of inflammatory pain.
Topics: Animals; Humans; Hyperalgesia; Inflammation; Neurons, Afferent; Receptors, Proteinase-Activated
PubMed: 15962118
DOI: 10.1590/s0074-02762005000900029 -
NeuroImage May 2021Neural networks involved in placebo analgesia and nocebo hyperalgesia processes have been widely investigated with neuroimaging methods. However, few studies have... (Meta-Analysis)
Meta-Analysis
Neural networks involved in placebo analgesia and nocebo hyperalgesia processes have been widely investigated with neuroimaging methods. However, few studies have directly compared these two processes and it remains unclear whether common or distinct neural circuits are involved. To address this issue, we implemented a coordinate-based meta-analysis and compared neural representations of placebo analgesia (30 studies; 205 foci; 677 subjects) and nocebo hyperalgesia (22 studies; 301 foci; 401 subjects). Contrast analyses confirmed placebo-specific concordance in the right ventral striatum, and nocebo-specific concordance in the dorsal anterior cingulate cortex (dACC), left posterior insula and left parietal operculum during combined pain anticipation and administration stages. Importantly, no overlapping regions were found for these two processes in conjunction analyses, even when the threshold was low. Meta-analytic connectivity modeling (MACM) and resting-state functional connectivity (RSFC) analyses on key regions further confirmed the distinct brain networks underlying placebo analgesia and nocebo hyperalgesia. Together, these findings indicate that the placebo analgesia and nocebo hyperalgesia processes involve distinct neural circuits, which supports the view that the two phenomena may operate via different neuropsychological processes.
Topics: Analgesia; Brain; Brain Mapping; Humans; Hyperalgesia; Magnetic Resonance Imaging; Nerve Net; Nocebo Effect; Pain; Placebo Effect; Positron-Emission Tomography
PubMed: 33549749
DOI: 10.1016/j.neuroimage.2021.117833 -
Neurogastroenterology and Motility Sep 2017Abdominal pain is associated with many gastrointestinal dysfunctions, such as irritable bowel syndrome (IBS), functional dyspepsia, and inflammatory bowel disease (IBD).... (Review)
Review
Abdominal pain is associated with many gastrointestinal dysfunctions, such as irritable bowel syndrome (IBS), functional dyspepsia, and inflammatory bowel disease (IBD). Visceral hypersensitivity is a key reason for development of abdominal pain that presents in these gastrointestinal disorders/diseases. The pathogenesis of visceral hypersensitivity is complex and still far from being fully understood. In animal studies, visceral hypersensitivity has been linked to several early-life adverse (ELA) events. In humans, IBD, functional dyspepsia, and IBS can have adult onset, though the adverse events that lead to visceral hypersensitivity are largely uncharacterized. In this issue of the journal, Aguirre et al. report the interesting finding that epigenetics underlies the effects of ELA events on visceral hypersensitivity. This mini-review examines models of ELA events leading to visceral hypersensitivity and the potential role of epigenetics, as reported by Aguirre et al. and others.
Topics: Abdominal Pain; Animals; Epigenesis, Genetic; Humans; Hyperalgesia; Stress, Psychological; Visceral Pain
PubMed: 28782197
DOI: 10.1111/nmo.13170 -
Molecular Pain May 2015Chronic pain is a major public health problem with limited treatment options. Opioids remain a routine treatment for chronic pain, but extended exposure to opioid... (Review)
Review
Chronic pain is a major public health problem with limited treatment options. Opioids remain a routine treatment for chronic pain, but extended exposure to opioid therapy can produce opioid tolerance and hyperalgesia. Although the mechanisms underlying chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia remain to be uncovered, mammalian target of rapamycin (mTOR) is involved in these disorders. The mTOR complex 1 and its triggered protein translation are required for the initiation and maintenance of chronic pain (including cancer pain) and opioid-induced tolerance/hyperalgesia. Given that mTOR inhibitors are FDA-approved drugs and an mTOR inhibitor is approved for the treatment of several cancers, these findings suggest that mTOR inhibitors will likely have multiple clinical benefits, including anticancer, antinociception/anti-cancer pain, and antitolerance/hyperalgesia. This paper compares the role of mTOR complex 1 in chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia.
Topics: Analgesics, Opioid; Animals; Chronic Pain; Drug Tolerance; Humans; Hyperalgesia; Pain Threshold; TOR Serine-Threonine Kinases
PubMed: 26024835
DOI: 10.1186/s12990-015-0030-5