Increased Pain Sensitivity Research Articles

Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain

The prevalence of chronic widespread pain (CWP) in people with HIV is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin, within their endoplasmic reticulum (ER). When released into plasma, β-endorphin dampens nociception by binding to opioid receptors on sensory neurons. We hypothesized that the heme-dependent redox signaling induces ER stress, which attenuates leukocyte β-endorphins levels/release, thereby increasing pain sensitivity in people with HIV. Results demonstrated that HIV positive individuals with CWP had increased plasma methemoglobin, erythrocytes membrane oxidation, hemolysis, and low plasma heme scavenging enzyme, hemopexin, compared to people with HIV without CWP and HIV-negative individuals with or without pain. In addition, the leukocytes from people with HIV with CWP had attenuated levels of the heme metabolizing enzyme, heme oxygenase-1, which metabolizes free heme to carbon-monoxide and biliverdin. These individuals also had elevated ER stress, and low β-endorphin in leukocytes. In vitro, heme exposure or heme oxygenase-1 deletion, decreased β-endorphins in murine monocytes/macrophages. Treating cells with a carbon-monoxide donor or an ER stress inhibitor, increased β-endorphins. To mimic hemolytic effects in a preclinical model, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-endorphin levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with hemopexin blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-endorphin is responsible for hypersensitivity in people with HIV.

Activation of HDAC4 and GR signaling contributes to stress-induced hyperalgesia in the medial prefrontal cortex of rats

“Stress-induced hyperalgesia (SIH)” is a phenomenon that stress can lead to an increase in pain sensitivity. Epigenetic mechanisms have been known to play fundamental roles in stress and pain. Histone acetylation is an epigenetic feature that is changed in numerous stress-related disease situations. However, epigenetic mechanism for SIH is not well known. We investigated the effect of histone acetylation on pain hypersensitivity using SPS (single-prolonged stress) + CFA (complete Freund’s adjuvant) model. We showed that the glucocorticoid receptor (GR)-pERK-pCREB-Fos signaling pathway was upregulated on stress-induced hyperalgesia and the paw withdrawal threshold in the SPS + CFA group dropped significantly compared with the SPS or CFA group. Histone deacetylases 4 (HDAC4)-expressing neurons in the medial prefrontal cortex (mPFC) were increased in the SPS + CFA-exposed group compared with CFA-exposed or SPS-exposed group. And we showed that the effects of stress-induced hyperalgesia were critically regulated via reversible acetylation (HDAC4) of the GR. Inhibiting HDAC4 by microinjection of sodium butyrate into the mPFC could disrupt glucocorticoid receptor (GR) signaling pathway, which lowered SPS + CFA-caused mechanical allodynia and alleviated anxiety-like behavior. Together, our studies suggest that HDAC inhibitors might involve in the process of stress-induced hyperalgesia.

Low maternal licking/grooming stimulation increases pain sensitivity in male mouse offspring.

Deprivation of maternal care has been associated with higher pain sensitivity in offspring. In the present study, we hypothesized that the maternal licking/grooming behavior was an important factor for the development of the pain regulatory system. To test this hypothesis, we used male F2 offspring of early-weaned (EW) F1 mother mice that exhibit lower frequency of licking/grooming behavior. The formalin test revealed that F2 offspring of EW F1 dams showed significantly higher pain behavior than F2 offspring of normally-weaned (NW) F1 dams. We found that the mRNA levels of transient receptor potential vanilloid 1 (TRPV1), a nociceptor, were higher in the lumbosacral dorsal root ganglion (DRG) of F2 offspring of EW F1 dams than those of F2 offspring of NW F1 dams, suggesting that the higher pain sensitivity may be attributed to low licking/grooming, which may result in developmental changes in nociceptive neurons. In the DRG, mRNA levels of Mas-related G-protein coupled receptor B4 (MrgprB4), a marker of sensory neurons that detect gentle stroking, was also up-regulated in the F2 offspring of EW F1 dams. Considering that gentle touch alleviates pain, Mrgprb4 up-regulation may reflect a compensatory change. The present findings indicate important implications of maternal licking/grooming behavior in the development of the pain regulatory system.

A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans

The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in ∼0.4% of present-day Britons, where they are associated with heightened pain sensitivity.

Pressure-Induced Referred Pain as a Biomarker of Pain Sensitivity in Fibromyalgia

Fibromyalgia (FM) syndrome is characterized by widespread pain, fatigue, and generalized increased pain sensitivity. Appropriate and simple pain models are methods employed to assess pain mechanisms that can potentially lead to improved treatments. Pressure pain thresholds (PPTs) or mapping the referred pain area produced by pressure stimulation at suprathreshold intensities are used to assess pain mechanisms. The optimal suprathreshold stimulation intensity to elicit referred pain with minimal discomfort for patients with FM has yet to be determined. The aim of this study was to compare the area and intensity of pressure-induced referred pain in patients with FM as elicited by systematic increases in PPTs, compared with controls. Observational, crossed-section study. Research laboratory. Twenty-six patients with FM and 26 healthy controls, age- and gender-matched, were included. Suprathreshold stimulation was applied to the infraspinatus muscle of the dominant side at 4 different intensities (PPT +20%, +30%, +40%, and +50%), after which referred pain was evaluated by measuring the area of pain in pixels using a digital body chart and its intensity on a Visual Analog Scale. Factors related to anxiety condition, pain catastrophizing, depression, and quality of life were recorded. The referred pain areas were larger in the FM group compared with healthy individuals at 120% (P = 0.024), 130% (P = 0.001), 140% (P = 0.001), and 150% (P = 0.001) PPT, however, within the FM group no differences were found between the intensity of suprathreshold stimulation and the size of the referred pain areas (P = 0.135) or pain intensity (P > 0.05). There was a positive correlation between the size of referred pain areas and pain catastrophizing in the FM group (r = 0.457, P = 0.032). This study presents some limitations, among which is the variability found in the referred pain areas. These findings show that referred pain induced by applying a suprathreshold pressure of 120% PPT can be a useful biomarker to assess sensitized pain mechanisms in patients suffering from FM. Referred pain, pain sensitivity, fibromyalgia, central sensitization, suprathreshold, pressure pain threshold, biomarker, facilitated pain mechanisms.

Pressure pain threshold and temporal summation in adults with episodic and persistent low back pain trajectories: a secondary analysis at baseline and after lumbar manipulation or sham

BackgroundPeople with chronic low back pain (LBP) typically have increased pain sensitivity compared to healthy controls, however its unknown if pain sensitivity differs based on LBP trajectory at baseline or after manual therapy interventions. We aimed to compare baseline pressure pain threshold (PPT) and temporal summation (TS) between people without LBP, with episodic LBP, and with persistent LBP, and to compare changes over time in PPT and TS after a lumbar spinal manipulation or sham manipulation in those with LBP.MethodsParticipants were aged 18–59, with or without LBP. Those with LBP were categorised as having either episodic or persistent LBP. PPT and TS were tested at baseline. LBP participants then received a lumbar spinal manipulation or sham, after which PPT and TS were re-tested three times over 30 min. Generalised linear mixed models were used to analyse data.ResultsOne hundred participants (49 female) were included and analysed. There were 20 non-LBP participants (mean age 31 yrs), 23 episodic LBP (mean age 35 yrs), and 57 persistent LBP (mean age 37 yrs). There were no significant differences in PPT or TS between groups at baseline. There was a non-significant pattern of lower PPT (higher sensitivity) from the non-LBP group to the persistent LBP group at baseline, and high variability. Changes in PPT and TS after the interventions did not differ between the two LBP groups.DiscussionWe found no differences between people with no LBP, episodic LBP, or persistent LBP in baseline PPT or TS. Changes in PPT and TS following a lumbar manual therapy intervention do not appear to differ between LBP trajectories.Trial registrationThe trial was prospectively registered with ANZCTR (ACTRN12617001094369).

Interaction of auditory and pain pathways: Effects of stimulus intensity, hearing loss and opioid signaling

Moderate intensity sounds can reduce pain sensitivity (i.e., audio-analgesia) whereas intense sounds can induce aural pain, evidence of multisensory interaction between auditory and pain pathways. To explore auditory-pain pathway interactions, we used the tail-flick (TF) test to assess thermal tail-pain sensitivity by measuring the latency of a rat to remove its tail from 52 °C water. In Experiment 1, TF latencies were measured in ambient noise and broadband noise (BBN) presented from 80 to 120 dB SPL. TF latencies gradually increased from ambient to 90 dB SPL (audio-analgesia), but then declined. At 120 dB, TF latencies were significantly shorter than normal, evidence for audio-hyperalgesia near the aural threshold for pain. In Experiment II, the opioid pain pathway was modified by treating rats with a high dose of fentanyl known to induce post-treatment hyperalgesia. TF latencies in ambient noise were normal 10-days post-fentanyl. However, TF latencies became shorter than normal from 90 to 110 dB indicating that fentanyl pre-treatment had converted audio-analgesia to audio-hyperalgesia. In Experiment III, we tested the hypothesis that hearing loss could alter pain sensitivity by unilaterally exposing rats to an intense noise that induced a significant hearing loss. TF latencies in ambient noise gradually declined from 1- to 4-weeks post-exposure indicating that noise-induced hearing loss had increased pain sensitivity. Our results suggest that auditory and pain pathways interact in ways that depend on intensity, hearing loss and opioid pain signaling, results potentially relevant to pain hyperacusis.

PD-1 blockade inhibits osteoclast formation and murine bone cancer pain.

Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1-/-) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1-/- mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1-/- mice. Consistently, these beneficial effects in Pd1-/- mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.

Optimization of a rat lumbar IVD degeneration model for low back pain.

IntroductionIntervertebral disc (IVD) degeneration is often associated with low back pain and radiating leg pain. The purpose of this study is to develop a reproducible and standardized preclinical model of painful lumbar IVD degeneration by evaluation of structural and behavioral changes in response to IVD injury with increasing needle sizes. This model can be used to develop new therapies for IVD degeneration.MethodsForty‐five female Sprague Dawley rats underwent anterior lumbar disc needle puncture at levels L4‐5 and L5‐6 under fluoroscopic guidance. Animals were randomly assigned to four different experimental groups: needle sizes of 18 Gauge (G), 21G, 23G, and sham control. To monitor the progression of IVD degeneration and pain, the following methods were employed: μMRI, qRT‐PCR, histology, and biobehavioral analysis.ResultsT1‐ and T2‐weighted μMRI analysis showed a correlation between the degree of IVD degeneration and needle diameter, with the most severe degeneration in the 18G group. mRNA expression of markers for IVD degeneration markers were dysregulated in the 18G and 21G groups, while pro‐nociceptive markers were increased in the 18G group only. Hematoxylin and Eosin (H&E) and Alcian Blue/Picrosirius Red staining confirmed the most pronounced IVD degeneration in the 18G group. Randall‐Selitto and von Frey tests showed increased hindpaw sensitivity in the 18G group.ConclusionOur findings demonstrate that anterior disc injury with an 18G needle creates severe IVD degeneration and mechanical hypersensitivity, while the 21G needle results in moderate degeneration with no increased pain sensitivity. Therefore, needle sizes should be selected depending on the desired phenotype for the pre‐clinical model.

Plasma protein patterns are strongly correlated with pressure pain thresholds in women with chronic widespread pain and in healthy controls-an exploratory case-control study.

Chronic widespread pain (CWP) is a complex pain condition characterized by generalized musculoskeletal pain and often associated with other symptoms. An important clinical feature is widespread increased pain sensitivity such as lowered pain thresholds for mechanical stimuli (pressure pain thresholds [PPT]). There is a growing interest in investigating the activated neurobiological mechanisms in CWP, which includes fibromyalgia. In CWP, strong significant correlations have been found between muscle protein patterns and PPT. This explorative proteomic study investigates the multivariate correlation pattern between plasma proteins and PPT in CWP and in healthy controls (CON). In addition, this study analyses whether the important proteins for PPT differ between the 2 groups.Using 2-dimensional gel electrophoresis, we analyzed the plasma proteome of the CWP (n = 15) and the CON (n = 23) and proteins were identified using mass spectrometry. For both the CWP and the CON, the associations between the identified proteins and PPT were analyzed using orthogonal partial least square in 2 steps.Significant associations between certain plasma proteins and PPT existed both in CWP (R = 0.95; P = .006) and in CON (R = 0.89; P < .001). For both groups of subjects, we found several proteins involved in PPT that reflect different biological processes. The plasma proteins as well as the biological processes involved in PPT differed markedly between the 2 groups of subjects.This study suggests that plasma protein patterns are associated with pain thresholds in CWP. Using the plasma proteome profile of CWP to study potential biomarker candidates could provide a snapshot of ongoing systemic mechanisms in CWP.

Pain and dyskinesia in Parkinson's disease may share common pathophysiological mechanisms – An fMRI study

BackgroundParkinson's disease (PD) patients develop levodopa induced dyskinesia with disease progression from sensitization of central pathways. Pain pathways are also impacted with suggestions dyskinetic patients may process pain differently. ObjectiveEstablish if centrally sensitized nociceptive pathways are altered and dopaminergically driven in dyskinetic patients. MethodsClinical characteristics, affect, pain thresholds and sensitivity to pressure stimulation in the ON and OFF medication states as well as distribution of pain related activation of cortical regions on BOLD fMRI were assessed and compared between groups of patients suffering from dyskinesia and not. ResultsDyskinetic PD participants experienced increased pressure pain sensitivity. This was associated with increased pressure induced pain>innocuous BOLD activity in areas associated with encoding pain intensity, pain spatial orientation, descending pain mediation, sensorimotor integration, and motor control. Levodopa reduced pressure pain ratings and improved negative affect, though did not impact BOLD activity differently between the groups. ConclusionDyskinetic PD patients experience increased pain sensitivity and centrally sensitized nociceptive pathways resembling levodopa induced sensitization though this is not directly influenced by dopamine.

1215 Improving Sleep Disorders And Chronic Neck Pain By Adjusting Height Of The Pillow Through Cervical Posture Management

Abstract Introduction Recent studies have suggested that chronic musculoskeletal system pain, including chronic neck pain, accounts for approximately 70% of all sleeping disorders. Simultaneously, sleeping disorders increase pain sensitivity and create a vicious cycle of chronic neck pain. Patients with chronic pain experience a variety of somatic symptoms (e.g., Stomach or bowel problems, Back pain, Pain in your joints, headaches, chest pain, shortness of breath, dizziness, fatigue, and Trouble sleeping) that are difficult to treat. However, treatment of both neck chronic pain and sleeping disorders through cervical posture management by adjusting height of the pillow used while sleeping has yet to be considered. Methods Patients who visited our hospital with chief complaints of chronic neck pain were rated according to the Numerical Rating Scale (NRS) and were asked to answer the Somatic Symptom Scale-8 (SSS-8), to ascertain the degree of somatic symptoms. Out of all the patients, only 84 scored at least 8 out of 32 in the SSS-8. Based on the individual results of the 84 respondents, they were given customized pillows to be used for 3 months. The pillows were adjusted using the SSS method developed at our clinic. We adjusted the height of the pillow by 5mm increments to check the cervical inclination angle at approximately 15 degrees in supine position, lateral position with the center line from face to neck at left-right symmetry and finally confirming smooth turning over. The respondents performed NRS and SSS-8 after 2 weeks and 3 months of using the pillow. Results The results of this study showed that at 0 weeks / 2 weeks / 3 months. NRS score was 6.8 / 5.1 / 4.1 (p &amp;lt;0.01), and the overall SSS-8 score was 13.2 / 9.9 / 8.2 (p &amp;lt;0.01), showed a marked improvement. By symptom, all symptoms except Stomach or bowel problems showed significant improvement. Trouble sleeping showed the highest improvement at 2.6 / 1.7 / 1.3 (p &amp;lt;0.01). Conclusion Chronic neck pain and sleeping disorders improved in the patients. These results suggested that cervical posture management by adjusting height of the pillow is an effective treatment method. Support None

Chronic Morphine-Induced Changes in Signaling at the A3 Adenosine Receptor Contribute to Morphine-Induced Hyperalgesia, Tolerance, and Withdrawal.

Treating chronic pain by using opioids, such as morphine, is hampered by the development of opioid-induced hyperalgesia (OIH; increased pain sensitivity), antinociceptive tolerance, and withdrawal, which can contribute to dependence and abuse. In the central nervous system, the purine nucleoside adenosine has been implicated in beneficial and detrimental actions of morphine, but the extent of their interaction remains poorly understood. Here, we demonstrate that morphine-induced OIH and antinociceptive tolerance in rats is associated with a twofold increase in adenosine kinase (ADK) expression in the dorsal horn of the spinal cord. Blocking ADK activity in the spinal cord provided greater than 90% attenuation of OIH and antinociceptive tolerance through A3 adenosine receptor (A3AR) signaling. Supplementing adenosine signaling with selective A3AR agonists blocked OIH and antinociceptive tolerance in rodents of both sexes. Engagement of A3AR in the spinal cord with an ADK inhibitor or A3AR agonist was associated with reduced dorsal horn of the spinal cord expression of the NOD-like receptor pyrin domain-containing 3 (60%-75%), cleaved caspase 1 (40%-60%), interleukin (IL)-1β (76%-80%), and tumor necrosis factor (50%-60%). In contrast, the neuroinhibitory and anti-inflammatory cytokine IL-10 increased twofold. In mice, A3AR agonists prevented the development of tolerance in a model of neuropathic pain and reduced naloxone-dependent withdrawal behaviors by greater than 50%. These findings suggest A3AR-dependent adenosine signaling is compromised during sustained morphine to allow the development of morphine-induced adverse effects. These findings raise the intriguing possibility that A3AR agonists may be useful adjunct to opioids to manage their unwanted effects. SIGNIFICANCE STATEMENT: The development of hyperalgesia and antinociceptive tolerance during prolonged opioid use are noteworthy opioid-induced adverse effects that reduce opioid efficacy for treating chronic pain and increase the risk of dependence and abuse. We report that in rodents, these adverse effects are due to reduced adenosine signaling at the A3AR, resulting in NOD-like receptor pyrin domain-containing 3-interleukin-1β neuroinflammation in spinal cord. These effects are attenuated by A3AR agonists, suggesting that A3AR may be a target for therapeutic intervention with selective A3AR agonist as opioid adjuncts.

No Evidence of Altered Reactivity to Experimentally Induced Pain Among Regular Cannabis Users.

Recent years have seen an increase in the adoption of cannabinoid medicines, which have demonstrated effectiveness for the treatment of chronic pain. However, the extent to which frequent cannabis use (CU) influences sensitivity to acute pain has not been systematically examined. Such a determination is clinically relevant in light of hypersensitivity to pain associated with prolonged use of other analgesics such as opioids, and reports of increased pain sensitivity to experimentally induced pain during acute cannabis intoxication. This study explored differences in measures of pain intensity and tolerance. The authors hypothesized that individuals who report frequent CU would demonstrate greater experimental pain sensitivity. Frequent cannabis users (≥3× per week; n=40) and nonusers (n=40) were compared on pain sensitivity, pain tolerance, and pain intensity in response to a cold-pressor task. Group differences were examined. Frequent CU was not associated with hyperalgesia as cannabis users and nonusers did not exhibit differences on measures of pain tolerance (t (78)=-0.05; P=0.96), sensitivity (t (78)=-0.83; P=0.41), or intensity (t (78)=0.36; P=0.72). Frequent cannabis users did not demonstrate hyperalgesia. This finding should help to inform evaluations of the relative harms and benefits of cannabis analgesic therapies.

Impaired mesocorticolimbic connectivity underlies increased pain sensitivity in chronic low back pain

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP.

Changes of Somatosensory Phenotype in the Course of Disease in Osteoarthritis Patients.

To investigate sensory changes, physical function (pF), quality of life (QoL) and pain intensity of patients with osteoarthritis (OA) in the natural course of disease, and patients undergoing total joint replacement therapy (TJR) 31 (20 females, mean age 64.6 ± 10.4 years), patients with OA were investigated with questionnaires and quantitative sensory testing (QST) in the area of referred pain at the thigh at baseline and follow-up 22–49 weeks later; changes were analyzed separately for patients with (n = 13) and without TJR (n = 18). In patients without TJR pain intensity, pF, QoL did not improve, and increased pain sensitivity to cold and a stronger loss of detection were observed. In patients after TJR, however, a reduction in mechanical pain sensitivity and allodynia occurred in accordance with a reduction of pain intensity and improvement of functionality while QoL did not improve. Additionally, an increased sensitivity to heat pain and a more pronounced loss of mechanical detection could be observed in this group. TJR seems to stop peripheral pain input leading to a reduction of pain intensity and central sensitization, but surgery-induced sensory changes such as peripheral sensitization and loss of detection occur. Furthermore, TJR has favorable effects on pain intensity and functionality but not QoL.

High Frequency of the Opioid Receptor µ-1 (OPRM1) A118G Polymorphism, an Opioid Drug Therapy Related Gene, in the Indonesian Population

Background: The opioid receptor μ-1 (OPRM1) has become one of the most studied genes in pharmacogenetics, as this gene encodes the μ-opioid receptor (MOR), which plays a role in opioid drugs response, as well as in various disorders. One of its variants, A118G, which is found at a high frequency in the Asian population, has been associated with loss of sensitivity to and an increased requirement for analgesics in the treatment of pain, increased pain sensitivity, various types of substance dependencies, and the development of breast cancer. However, there are still limited reports about this gene polymorphism in the Indonesian population. Objective: The study aimed to determine the allele frequencies of the OPRM1 A118G polymorphism among the Indonesian population. Method: A cross-sectional study of 158 subjects, comprising 79 males and 79 females, was conducted among Indonesians, and genotype analysis was carried out by a modified allele-specific Polymerase Chain Reaction (PCR) method. Results: A frequency of 60.4% was found for the G allele among Indonesian samples, with a higher frequency being present in males (66.5%). The A allele was found at frequencies of 33.5% and 45.6% in males and females, respectively. A significant difference in allele frequency was found between males and females (p = 0.029, OR = 1.659, 95% CI [1.052–2.614]), while there was no significant difference in genotype frequencies between groups. Conclusion: A high prevalence of the OPRM1 A118G polymorphism was found in the Indonesian population, with the G allele frequency tending to be higher in males.

Abnormal Reinnervation of Denervated Areas Following Nerve Injury Facilitates Neuropathic Pain.

An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the denervated skin could contribute to the development of neuropathic pain. Here, we examined the changes in the innervation pattern during reinnervation and correlated them with the symptoms of neuropathic pain. Using a multispectral labeling technique—PainBow, which we developed, we characterized dorsal root ganglion (DRG) neurons innervating distinct areas of the rats’ paw. We then used spared nerve injury, causing partial denervation of the paw, and examined the changes in innervation patterns of the denervated areas during the development of allodynia and hyperalgesia. We found that, differently from normal conditions, during the development of neuropathic pain, these areas were mainly innervated by large, non-nociceptive neurons. Moreover, we found that the development of neuropathic pain is correlated with an overall decrease in the number of DRG neurons innervating these areas. Importantly, treatment with ouabain facilitated reinnervation and alleviated neuropathic pain. Our results suggest that local changes in peripheral innervation following denervation contribute to neuropathic pain development. The reversal of these changes decreases neuropathic pain.

Mechanical allodynia in mice with tenascin-X deficiency associated with Ehlers-Danlos syndrome

Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising. TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. However, the molecular mechanisms by which TNX deficiency complicates pain are unknown. Here, we examined the nociceptive behavioral responses of TNX-deficient mice. Compared with wild-type mice, TNX-deficient mice exhibited mechanical allodynia but not thermal hyperalgesia. TNX deficiency also increased pain sensitivity to chemical stimuli and aggravated early inflammatory pain elicited by formalin. TNX-deficient mice were significantly hypersensitive to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not to stimuli at frequency of 5 Hz (C fiber responses). In addition, the phosphorylation levels of extracellular signal-related kinase, an active neuronal marker, and the activity of NADPH-diaphorase, a neuronal nitric oxide activation marker, were enhanced in the spinal dorsal horns of TNX-deficient mice. These results suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn.

Activation of sphingosine-1-phosphate receptor subtype 1 in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in rodents

Morphine-induced alterations in sphingolipid metabolism in the spinal cord and increased formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) have been implicated in the development of morphine-induced hyperalgesia (OIH; increased pain sensitivity) and antinociceptive tolerance. These adverse effects hamper opioid use for treating chronic pain and contribute to dependence and abuse. S1P produces distinct effects through 5 G-protein-coupled receptors (S1PR1-5) and several intracellular targets. How S1P exerts its effects in response to morphine remains unknown. Here, we report that S1P contributes to the development of morphine-induced hyperalgesia and tolerance through S1P receptor subtype 1 (S1PR1) signaling in uninjured male and female rodents, which can be blocked by targeting S1PR1 with S1PR1 antagonists or RNA silencing. In mouse neuropathic pain models, S1PR1 antagonists blocked the development of tolerance to the antiallodynic effects of morphine without altering morphine pharmacokinetics and prevented prolonged morphine-induced neuropathic pain. Targeting S1PR1 reduced morphine-induced neuroinflammatory events in the dorsal horn of the spinal cord: increased glial marker expression, mitogen-activated protein kinase p38 and nuclear factor κB activation, and increased inflammatory cytokine expression, such as interleukin-1β, a cytokine central in the modulation of opioid-induced neural plasticity. Our results identify S1PR1 as a critical path for S1P signaling in response to sustained morphine and reveal downstream neuroinflammatory pathways impacted by S1PR1 activation. Our data support investigating S1PR1 antagonists as a clinical approach to mitigate opioid-induced adverse effects and repurposing the functional S1PR1 antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.