Model Of Chronic Pain Research Articles

흰 쥐의 만성 통증모델에서 구강건조증이 c-fos 발현에 미치는 영향

Objectives: The purpose of this study was to determine whether xerostomia could improve the level of neuropathic pain. To conduct the study, the change in c-fos expression level in the medulla oblongata was confirmed by xerostomia induction using the chronic neuropathic facial pain model. Methods: mal-positioned dental implant surgery was performed on the extraction site of the mandibular second molar of rats, and 4-diphenylacetoxy-N- methylpiperidine (4-DAMP) (30mg/kg) was injected intraperitoneally after a pain test on the 4th day after surgery. c-fos was counted only in the lamina I and II regions. Results: A significant increase in c-fos expression was observed when the maxilla was stimulated compared to the mandible in the group induced both neuropathy and xerostomia. Conclusions: Therefore, it is considered that xerostomia in the facial area is the cause of the expression of chronic pain and the improvement of pain sensation.

Higenamine inhibits acute and chronic inflammatory pain through modulation of TRPV4 channels

Pain is the cardinal symptom of many debilitating diseases and results in heavy health and economic burdens worldwide. Asarum (Asarum sieboldii Miq.) is a commonly used analgesic in Chinese medicine. However, the analgesic components and mechanisms of asarum in acute and chronic pain mice model remain unknown. In this study, we first generated asarum water extract and confirmed strong analgesic properties in mice in both the acute thermal and mechanical pain models, as well as in the complete Freund's adjuvant (CFA) induced chronic inflammatory pain model. Second, we identified higenamine as a major component of asarum and found that higenamine significantly inhibited thermal and mechanical induced acute pain and CFA induced chronic inflammatory pain. Then, using Trpv4−/− mice, we found that TRPV4 is necessary for CFA induced thermal and mechanical allodynia, and demonstrated that higenamine analgesia in the CFA model is partly through TRPV4 channel inhibition. Finally, we found that GSK1016790A, a TRPV4 agonist, induced calcium response was significantly inhibited by higenamine in both cultured DRG neurons and TRPV4 transfected HEK293 cells. Consistent with calcium imaging results, higenamine pretreatment also dose-dependently inhibited GSK1016790A induced acute pain. Taken together, our behavior and calcium imaging results demonstrate that the asarum component higenamine inhibits acute and chronic inflammatory pain by modulation of TRPV4 channels.

Physical Activity, Social Participation, and Pain Outcomes Among Community-Dwelling Older Adults

BackgroundLittle is known regarding the effect of social participation (SP) and physical activity (PA) on pain outcomes among community-dwelling older adults in the United States. AimsTo determine whether SP and PA are associated with pain outcomes (bothersome pain and number of pain sites). DesignGuided by the biopsychosocial model of chronic pain for older adults, we analyzed data from 7,187 community dwelling participants in the National Health and Aging Trends Study. In cross-sectional analyses, we utilized logistic and negative binomial regressions. MethodsWe prospectively assessed the association between SP/ PA and new or worsening pain from baseline (2011) to 2021 using a discrete time survival analysis by logistic regression, controlling for sociodemographic and health characteristics. ResultsAt baseline, participation in 5 SP activities per month versus no activities, and performing any PA compared with no PA were significantly associated with lower likelihood of bothersome pain. Although SP and PA were associated with reporting fewer pain sites at baseline, SP was not associated with developing new or worsening pain, prospectively. However, walking and vigorous exercise compared with no PA was significantly associated with a 10% lower risk of developing new or worsening pain (adj odds ratio 0.90, 95% confidence interval [CI] 0.82-0.98). ConclusionsPhysical activity but not social participation may protect against development of new or worsening pain. More research is needed to determine whether social activity can be beneficial for pain prevention and management. Efforts to promote physical activity among older adults may reduce risk of new or worsening pain.

CCL2- and Notch2-mediated Central Sensitization in a Rat Chronic Pelvic Pain Model.

Chronic pelvic pain (CPP) is a common gynecological condition in women with multifactorial etiology. Some studies have revealed that patients with CPP have the same structural and functional changes in the pain matrix in the brain to patients with other types of chronic pain. However, the relationship between localized pelvic pain and changes in the structure and function of the central nervous system is still unclear. In this study, a rat model of CPP was established by pelvic nerve ligation and behavioral tests were used to validate the model. Afterwards, we compared the expression of CCL2 in CPP and control rats and observed the changes in their behavioral patterns by blocking the expression of CCL2 in the former group. In addition, we upregulated the expression of CCL2 in human microglia cells (HMC3) to further observe the effect of CCL2 on the Notch2 pathway. Our results showed that the expression of chemokine ligand 2 (CCL2) in the serum exosomes, pelvic vascular endothelial cells, and cerebrospinal fluid was higher in the CPP group than the control group (p<0.05). In HMC3 treated with recombinant CCL2 protein, a significant increase in the mRNA and protein expression of Notch2 was observed. CCL2 can activate the Notch2 signaling pathway and plays an important role in the central sensitization of chronic pelvic pain.

PSYCHOSOCIAL PHENOTYPES OF OLDER ADULTS WITH PAIN AND THEIR ASSOCIATED CLINICAL OUTCOMES

Abstract Older adults experience higher rates of pain than any other age group, with a domino effect on quality of life and well-being. Existing literature reveals associations between pain and adverse psychosocial, physical, and cognitive outcomes, with psychosocial variables linking all other aspects of well-being in older adults. Therefore, a comprehensive understanding of the associations of psychosocial variables with clinical outcomes in older adults with pain is needed. Grounded in the Biopsychosocial Model of Chronic Pain for Older Adults, we analyzed cross-sectional 2021 data from the nationally representative survey conducted by the National Health and Aging Trends Study. We performed latent class analysis to identify psychosocial clusters (including anxiety, depression, affect, self-realization, resilience, and social participation) of older adults with pain and then used multiple regression analyses to compare pain characteristics, physical health, and cognition among different clusters. We identified four clusters: “Intermediate Psychosocial Phenotype,” “Favorable Psychosocial Phenotype,” “Adverse Psychosocial Phenotype,” and “Compensated Psychosocial Adversity.” Clusters with more psychosocial adversity had worse pain, physical, and cognitive outcomes while controlling for race/ethnicity, gender, and age. Increased self-realization and resilience were seen in clusters with better clinical outcomes. Our findings provide important information for precision pain management interventions for older adults based on their psychosocial phenotypes. Further research should analyze longitudinal trajectories of psychosocial phenotypes as older adults’ pain experience progresses. Clinically, pain treatment decisions should include a comprehensive evaluation of psychosocial factors, with associated health policy initiatives aimed at assessing differences in care utilization and cost among older adults based on phenotype.

Stimulation of nuclear receptor REV-ERBs alleviates monosodium iodoacetate-induced osteoarthritis pathology of mice and the induction of inflammatory molecules expression in primary cultured chondrocytes

Because inflammation in chondrocytes contributes to the induction of osteoarthritis (OA), regulation of their activity is essential. A previous study showed that stimulation of the reverse erythroblastosis virus (REV-ERB) nuclear receptors in spinal glial cells elicits anti-inflammatory and antinociception effects in animal models of chronic pain. However, the involvement of REV-ERBs in chondrocyte functions and OA pathologies remains to be elucidated. In the current study, we found that pretreatment with the REV-ERB agonist SR9009 significantly blocked the increases in inflammatory molecules [(matrix metalloproteinase (MMP) 3, MMP9, and MMP13] and cytokines (interleukin-1β and tumor necrosis factor) in primary cultured chondrocytes following treatment with lipopolysaccharide. Furthermore, repeated intra-articular treatment with SR9009 significantly prevented monosodium iodoacetate-induced mechanical hypersensitivity and tended to partially reduce knee joint damage in mice. In conclusion, our findings suggest that REV-ERBs have a critical role in alleviating nociceptive hypersensitivity in OA pathologies by negatively regulating inflammation in chondrocytes.

Antinociceptive Effect of the Combination of a Novel α4β2* Agonist with Donepezil in a Chronic Pain Model.

Chronic pain presents a major challenge in contemporary medicine, given the limited effectiveness and numerous adverse effects linked to available treatments. Recognizing the potential of the cholinergic pathway as a therapeutic target, the present work evaluates the antinociceptive activity of a combination of Cris-104, a novel α4β2* receptor agonist, and donepezil, a central anticholinesterase agent. Isobolographic analysis revealed that equimolar combination was approximately 10 times more potent than theoretically calculated equipotent additive dose. Administration of Cris-104 and donepezil combination (3 μmol/kg) successfully reversed hyperalgesia and mechanical allodynia observed in rats subjected to spinal nerve ligation (SNL). The combination also modulated neuroinflammation by reducing astrocyte activation, evident in the decreased expression of glial fibrillary acidic protein (GFAP) in the spinal cord. The observed synergism in combining a nicotinic receptor agonist with an anticholinesterase agent underscores its potential for treating chronic pain. This alternative therapeutic distinct advantage, including dose reduction and high selectivity for the receptor, contribute to a more favorable profile with minimized adverse effects.

Intravenous psilocybin attenuates mechanical hypersensitivity in a rat model of chronic pain

There is a renewed interest in psychedelic drugs as potential therapeutic agents for the treatment of psychiatric disorders. In particular, psilocybin has shown promise for the treatment of refractory depression1 and major depressive disorder2, and has also been explored as a treatment for tobacco and alcohol abuse3,4. However, despite suggestive evidence5,6, there has been no systematic study to investigate the effectiveness of psilocybin in attenuating indices of chronic pain. To address this gap, we investigated the effect of psilocybin on mechanical hypersensitivity and thermal hyperalgesia in a well-established rat model of formalin-induced, centralized chronic pain7,8 and demonstrate that a single intravenous bolus administration of psilocybin can attenuate mechanical hypersensitivity for 28 days.

Sex differences in descending control of nociception (DCN) responses after chronic orofacial pain induction in rats and the contribution of kappa opioid receptors

Descending control of nociception (DCN), a measure of efficiency of descending pain inhibition, can be assessed in animals by the combined application of test and conditioning noxious stimuli. Evidence from pre-clinical and clinical studies indicates that this mechanism of pain control may differ between sexes and might be impaired in many chronic pain states. However, little is known about sex differences in DCN efficiency in models of acute and chronic orofacial pain. Herein, we first evaluated DCN responses in male and female rats by the applying formalin into the upper lip or capsaicin into the forepaw as the conditioning stimulus, followed by mechanical stimulation (Randall-Selitto) of the hind paw as the test stimulus. The same protocol (i.e., capsaicin in the forepaw followed by mechanical stimulation of the hind paw) was evaluated in male and female rats on day 3 after intraoral incision and on day 15 and 30 after chronic constriction injury of the infraorbital nerve (CCI-ION). Additionally, we assessed the effect of the kappa opioid receptor (KOR) antagonist Norbinaltorphimine (nor-BNI) on DCN responses of female nerve-injured rats. This study shows that naïve female rats exhibit less efficient DCN compared to males. Postoperative pain did not alter DCN responses in female and male rats, but CCI-ION induced loss of DCN responses in females but not in males. Systemic pretreatment with nor-BNI prevented the loss of DCN induced by CCI-ION in female rats. The results reveal sex differences in DCN responses and female-specific impairment of DCN following chronic orofacial pain. Moreover, the findings suggest that, at least for females, blocking KOR could be a promising therapeutic approach to prevent maladaptive changes in chronic orofacial pain.

Evaluation of the anti-nociceptive profile of essential oil from Melissa officinalis L. (lemon balm) in acute and chronic pain models

Ethnopharmacological relevanceMelissa officinalis L. (Lamiaceae) is a medicinal plant native to Mediterranean regions and found in other parts of the world. Extracts and essential oil from this widely cultivated culinary medicinal herb are used in traditional medicine to manage a variety of disorders that include epilepsy and pain. Aim of the studyTo assess the anti-nociceptive potentials of Melissa officinalis essential oil (MO) and probe the involvement of adrenergic, opioidergic, serotonergic and potassium adenosine triphosphate (KATP) mechanisms in its anti-nociceptive effects. Material and methodsWe employed formalin-, acetic acid and hot plate-induced nociception to study the acute anti-nociceptive effects of MO. The sciatic nerve injury (CCI) model of neuropathic pain was utilized to study the anti-nociceptive effects of MO on chronic pain. Effects of MO on anxiety, cognitive deficits, oxidative stress and inflammation in the CCI rats were evaluated on elevated plus maze, open field test, novel object recognition, oxidative stress parameters and pro-inflammatory cytokines, respectively. The possible mechanism(s) of MO's anti-nociceptive effects were elucidated using prazosin, yohimbine, propranolol, glibenclimide, naloxone and metergoline, which are acknowledged antagonists for α1–, α2– and β–adrenergic, potassium adenosine triphosphate (KATP), opioidergic and serotonergic systems, respectively. ResultsMO significantly attenuated acetic acid- and formalin-induced nociception; prolonged the mean reaction time of rats on hot plate before and following sciatic nerve chronic injury (CCI). MO ameliorated anxiety, cognitive deficits and oxidative stress, reduced pro-inflammatory cytokine levels and produced a near total restoration of injured sciatic nerves in CCI rats. Naloxone, metergoline and glibenclimide significantly blocked, while prazosin, yohimbine and popranolol failed to block the anti-nociceptive effects of MO in formalin-induced nociception. ConclusionsMO contains biologically active compounds with potential anti-nociceptive properties that modulate KATP, opioidergic and serotonergic pathways. These support the development of bioactive compounds from MO as anti-nociceptive agents.

Orexin receptors in the hippocampal dentate gyrus modulated the restraint stress-induced analgesia in the animal model of chronic pain

Previous studies have shown that stressful stimuli induced an adaptive response of reduced nociception, known as stress-induced analgesia (SIA). Since orexin neuropeptides are involved in pain modulation, and orexin neurons, primarily located in the lateral hypothalamus (LH), project to various hippocampal regions, such as the dentate gyrus (DG), the current study aimed to examine the role of orexin receptors within the DG region in the restraint SIA in the animal model of chronic pain. One hundred-thirty adult male Wistar rats (230–250 g) were unilaterally implanted with a cannula above the DG region. Animals were given SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol, 0.5 µl/rat) into the DG region as orexin-1 receptor (OX1r) and orexin-2 receptor (OX2r) antagonists, respectively, five min before exposure to a 3-hour restraint stress (RS) period. Animals were then undergone the formalin test to assess pain-related behaviors as the animal model of chronic pain. The results showed that RS produces an analgesic response during the early and late phases of the formalin test. However, intra-DG microinjection of OX1r and OX2r antagonists attenuated the restraint SIA. OX2r antagonist was more potent than OX1r antagonist in the early phase of the formalin test, while OX1r antagonist was little more effective in the late phase. Predominantly, it could be concluded that the orexinergic system in the DG region might act as a potential endogenous pain control system and a novel target for treating stress-related disorders.

Electroacupuncture Stimulation Alleviates Inflammatory Pain in Male Rats by Suppressing Oxidative Stress.

In the present study, we focused on whether the analgesic effect of Electroacupuncture (EA) is related to the regulation of oxidative stress. We established a chronic inflammatory pain model in male rats by a single injection of complete Freund's adjuvant (CFA) and then treated the animals with daily EA stimulation at the site of "zusanli". The analgesic effect of EA was evaluated by measuring the paw withdrawal threshold (PWT) when rats received mechanical and thermal pain stimulation. The levels of inflammation-related molecules and oxidative stress-related markers in the spinal cord were measured by western blotting or ELISA kits. EA stimulation and antioxidants effectively increased the PWT in CFA rats. Co-treatment of CFA rats with the ROS donor t-butyl hydroperoxide (t-BOOH) further decreased the PWT and weakened the analgesic effect of EA. EA treatment inhibited inflammation and oxidative stress, as shown by decreased levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and MDA and increased activity of SOD and catalase. Moreover, EA reduced the expression of p-p38, p-ERK, and p-p65 and simultaneously downregulated the expression of TRPV1 and TRPV4 in CFA rats. In an in vitro study, direct stimulation with t-BOOH to the C6 cells increased the production of TNF-alpha, IL-1beta, IL-6, activated p38, ERK, and p65 and up-regulated the expression of TRPV1 and TRPV4, and these effects could be prevented by the ROS scavenger PBN. Taken together, our data indicate that the inhibition of oxidative stress and the generation of ROS contribute to the analgesic effect of EA in male CFA rats.

Ninety-Hz Spinal Cord Stimulation–Induced Analgesia Is Dependent on Active Charge Balance and Is Nonlinearly Related to Amplitude: A Sham-Controlled Behavioral Study in a Rodent Model of Chronic Neuropathic Pain

BackgroundNinety-Hz active-recharge spinal cord stimulation (SCS) applied at below sensory-threshold intensity, as used with fast-acting subperception therapy spinal cord stimulation, has been shown clinically to produce significant analgesia, but additional characterization is required to better understand the therapy. This preclinical study investigates the behavioral effect of multiple 90-Hz SCS variants in a rodent model of neuropathic pain, focusing on charge balance and the relationship between 90-Hz efficacy and stimulation intensity. Materials and MethodsRats (n = 24) received a unilateral partial sciatic nerve ligation to induce neuropathic pain and were implanted with a quadripolar lead at T13. Mechanical hypersensitivity was assessed before, during, and after 60 minutes of SCS. After a prescreen with 50-Hz SCS 67% motor threshold ([MT], the positive control), rats underwent a randomized-crossover study including sham SCS and several 90-Hz SCS paradigms (at 40% MT or 60% MT, either using active or pseudopassive recharge) (experiment 1, n = 16). A second, identical experiment (experiment 2) was performed to supplement data with 90-Hz SCS at 20% and 80% MT (experiment 2, n = 8). ResultsExperiment 1: At 40% MT, 90-Hz active-recharge SCS produced a significantly larger recovery to baseline than did 90-Hz pseudopassive SCS at both tested intensities and sham SCS. Experiment 2: Only the 90-Hz SCS active recharge at 40% MT and 50-Hz SCS positive control caused mean recovery to baseline that was statistically better than that of sham SCS. ConclusionsThe degree to which 90-Hz SCS reduced mechanical hypersensitivity during stimulation depended on the nature of charge balance, with 90-Hz active-recharge SCS generating better responses than did 90-Hz pseudopassive recharge SCS. In addition, our findings suggest that the amplitude of 90-Hz active-recharge SCS must be carefully configured for efficacy.

Andrographolide inhibits the activation of spinal microglia and ameliorates mechanical allodynia.

Andrographolide (Andro), a labdane diterpene, possesses anti-inflammatory properties and has been used to treat numerous inflammatory diseases. Novel findings revealed that Andro might be vital in regulating pain. However, the contribution of Andro to chronic inflammatory pain has yet to be determined, and its underlying mechanism of action remains unknown. In this study, we observed that Andro attenuated mechanical allodynia in inflammatory pain mice induced by injecting complete Freund's adjuvant (CFA) into the right hind paws. This analgesic effect of Andro is mainly dependent on its inhibition of microglial overactivation and the release of proinflammatory cytokines (TNF and IL-1β) in lumbar spinal cords of inflammatory pain model mice. More importantly, our data in vivo and in vitro revealed a negative role for Andro in regulating the TLR4/NF-κB signaling pathway, which might contribute to the inhibition of spinal microglial activation and proinflammatory cytokines production, and the improvement of paw withdrawal thresholds in a mouse model of chronic inflammatory pain evoked by CFA. We further found the potential interaction of Andro with TLR4/myeloid differentiation factor 2 heterodimer using molecular modeling, implying that TLR4 might be a potential target for Andro to exert an analgesic effect. Taken together, our findings demonstrated that the modulation of spinal microglial activation by Andro might be substantially conducive to managing chronic pain triggered by neuroinflammation.

Inhibition of spinal Rac1 attenuates chronic inflammatory pain by regulating the activation of astrocytes

BackgroundSpinal astrocyte-mediated neuroinflammation is an important mechanism for the maintenance of chronic inflammatory pain. Previous studies have investigated that Ras-related C3 botulinum toxin substrate 1 (Rac1) is closely related to astrocyte activation after central nervous system injury. However, the role of Rac1 in astrocyte activation in chronic inflammatory pain has not been reported. MethodsComplete Freund's adjuvant (CFA)-induced chronic inflammatory pain model and LPS-stimulated astrocytes were used to investigate the role of Rac1 in astrocyte activation and the underlying mechanism. Rac1-interfering adeno-associated virus (AAV) targeting astrocytes was delivered to spinal astrocytes by intrathecal administration and a Rac1 specific inhibitor, NSC23766, was used to block cultured astrocytes. The glial fibrillary acidic protein (GFAP), proinflammatory cytokines, p-NF-κB, and nod-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome were detected by RT-qPCR, Western blotting, and immunofluorescence to investigate the activation of astrocytes. ResultsCFA induced spinal astrocyte activation and increased the expression of active Rac1 in spinal astrocytes. Knockdown of astrocyte Rac1 alleviated chronic inflammatory pain and inhibited astrocyte activation. Inhibition of Rac1 activation in cultured astrocytes decreased the expression of GFAP and proinflammatory cytokines. Knockdown of Rac1 inhibited the increase of expression of NLRP3 inflammasome and phosphorylation of NF-κB in the spinal lumbar enlargement after CFA injection. Similarly, the inhibition of Rac1 suppressed the increase of NLRP3 inflammasome and p-NF-κB protein level after LPS stimulation. ConclusionKnockdown of astrocyte Rac1 attenuated CFA-induced hyperalgesia and astrocyte activation possibly by blocking the expression of NLRP3 inflammasome and phosphorylation of NF-κB.

Adolescent ethanol exposure promotes mechanical allodynia and alters dopamine transmission in the nucleus accumbens shell.

Excessive alcohol consumption in adolescence can disrupt neural development and may augment pain perception. Recent studies have shown that the nucleus accumbens (NAc) shell is involved in mediating pain sensitivity after peripheral inflammation in rodent models of chronic pain and alcohol use disorder. Interestingly, there have been very few studies examining the impact of chronic ethanol exposure during adolescence on pain sensitivity in adulthood. Therefore, in this project, we investigated the impact of adolescent chronic intermittent ethanol (aCIE) exposure on mechanical allodynia. Furthermore, given the involvement of the NAc shell in pain processing and chronic ethanol-mediated changes, we measured changes in accumbal dopamine kinetics during protracted withdrawal. We found that both male and female aCIE rats show mechanical allodynia during withdrawal. Furthermore, male and female aCIE rats show greater evoked tonic dopamine release, maximal rate of dopamine reuptake, and dopamine affinity to the dopamine transporter in the NAc shell compared with controls. With phasic stimulation, aCIE rats also showed greater dopamine release compared with AIR-exposed rats. Inhibition of dopamine transmission targeted in the NAc shell reversed the aCIE-associated facilitation of mechanical allodynia in both sexes. These data suggest that aCIE exposure exacerbates pain sensitivity during withdrawal in an accumbal dopamine-dependent manner.

Elevated Serotonin in Mouse Spinal Dorsal Horn Is Pronociceptive.

Serotonergic neurons in the rostral ventral medulla (RVM) contribute to bidirectional control of pain through modulation of spinal and trigeminal nociceptive networks. Deficits in this pathway are believed to contribute to pathologic pain states, but whether changes in serotonergic mechanisms are pro- or antinociceptive is debated. We used a combination of optogenetics and fiber photometry to examine these mechanisms more closely. We find that optogenetic activation of RVM serotonergic afferents in the spinal cord of naive mice produces mechanical hypersensitivity and conditioned place aversion (CPA). Neuropathic pain, produced by chronic constriction injury of the infraorbital nerve (CCI-ION), evoked a tonic increase in serotonin (5HT) concentrations within the spinal trigeminal nucleus caudalis (SpVc), measured with liquid chromatography-tandem mass spectroscopy (LC-MS/MS). By contract, CCI-ION had no effect on the phasic serotonin transients in SpVc, evoked by noxious pinch, and measured with fiber photometry of a serotonin sensor. These findings suggest that serotonin release in the spinal cord is pronociceptive and that an increase in sustained serotonin signaling, rather than phasic or event driven increases, potentiate nociception in models of chronic pain.

Assessment of pain-related behaviors in HIV-1 transgenic rats as a model of HIV-associated chronic pain.

Human immunodeficiency virus-1 (HIV)-associated chronic pain is a debilitating comorbid condition that affects 25-85% of people with HIV. The use of opioids to alleviate pain has given rise to opioid dependency in this cohort. Therefore, there is an urgent need to understand mechanisms and identify novel therapeutics for HIV-associated chronic pain. Several animal models have been developed to study HIV-related comorbidities. HIV-1 transgenic (Tg) rats have been shown to serve as a reliable model that mimic the deficits observed in people with HIV, such as neurological and immune system alterations. However, pain-related behavior in these animals has not been extensively evaluated. In this study, we measured evoked and spontaneous behavior in HIV-1Tg male and female rats. The results indicated that HIV-1Tg rats exhibit similar behavior to those with HIV-1-related neuropathy, specifically, cold sensitivity. Consequently, HIV-1Tg rats can serve as a model of neuropathy to study pain-related mechanisms and therapeutics targeted toward individuals living with HIV-1.

Chronic Pain in the Lower Extremities and Low Back is Associated With Recurrent Falls in Community-Dwelling Japanese People Aged 40-74 Years

ObjectiveTo determine the longitudinal association between chronic pain in the lower extremities and low back and the odds of recurrent falls in middle-aged and older people. DesignA cohort study. SettingCommunities in Japan. ParticipantsParticipants were 7540 community-dwelling volunteers aged 40-74 years (N=7540). The baseline survey was a self-administered questionnaire conducted between 2011-2013. Predictors were presence of chronic pain in the knee, foot or ankle, and low back, with the degree of pain categorized as none, very mild/mild, moderate, or severe/very severe. Covariates in the multivariate model of chronic pain in a site were demographics, body mass index, physical activity level, disease history, and chronic pain in the other 2 sites. Logistic regression analysis was used to calculate odds ratios (ORs). InterventionsNone. Main Outcome Measure(s)Recurrent falls in the year before the 5-year follow-up survey. ResultsMean participant age was 60.2 years. Higher degrees of chronic pain were associated with higher odds of recurrent falls for the knee (P=.0002) with a higher OR of 1.48 (95% CI: 1.11-1.97), for the foot or ankle (P=.0001) with a higher OR of 1.97 (95% CI: 1.36-2.86), and for the low back (P=.0470) with a higher OR of 1.45 (95% CI: 1.09-1.91) in those with any degree of pain relative to those without pain. Higher degrees of chronic knee pain were associated with higher odds of recurrent falls in women (P=.0005), but not in men (P=.0813). Meanwhile, higher degrees of chronic low back pain were associated with the odds of recurrent falls in men (P=.0065), but not in women (P=.8735). ConclusionsChronic pain in the knee, foot or ankle, and lower back was independently and dose-dependently associated with a higher risk of recurrent falls. A marked sex-dependent difference was also noted in the association.

Complex Regional Pain Syndrome Type I: Evidence for the CB1 and CB2 Receptors Immunocontent and Beneficial Effect of Local Administration of Cannabidiol in Mice.

Introduction: Complex regional pain syndrome type I (CRPS-I) is a debilitating neuropathic painful condition associated with allodynia, hyperalgesia, sudomotor and/or vasomotor dysfunctions, turning investigation of its pathophysiology and new therapeutic strategies into an essential topic. We aim to investigate the impact of ischemia/reperfusion injury on the immunocontent of CB1 and CB2 cannabinoid receptor isoforms in the paws of mice submitted to a chronic postischemia pain (CPIP) model and the effects of local administration of cannabidiol (CBD) on mechanical hyperalgesia. Methods: Female Swiss mice, 30-35 g, were submitted to the CPIP model on the right hind paw. Skin and muscle samples were removed at different periods for western blot analysis. Results: No changes in the immunocontent of CB1 and CB2 receptors in paw muscle tissues after ischemia-reperfusion were observed. CBD promoted an antihyperalgesic effect in both phases. AM281 reversed the effect of CBD, whereas ruthenium red abolished the late phase. Conclusion: Our results point to the possible beneficial effects of local administration of CBD in modulating CRPS-I in humans. As possible targets for CBD antihyperalgesia in this model, the contribution of cannabinoid receptor CB1, in addition to TRPM8 is suggested.