Chronic Pain Behavior Research Articles

Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief

The blood-nerve barrier (BNB) is a selectively permeable barrier that creates an immunologically and biochemically privileged space for peripheral axons and supporting cells. The breakdown of the BNB allows access of blood-borne (hematogenous) cells and molecules to the endoneurium to engage in the local inflammatory cascade. This process was examined in a mouse model of trauma-associated neuropathic pain. The impact of nerve injury–triggered opening of the BNB in the development of chronic pain behavior was investigated. Partial ligation of the sciatic nerve led to a long-lasting disruption of the BNB distal to the site of injury. Vascular endothelial growth factor (VEGF) was expressed by resident macrophages after nerve injury. Intraneural injection of VEGF decreased mechanical thresholds while opening the BNB. Serum from nerve-injured or lipopolysaccharide-treated animals elicited mechanical allodynia in naive animals, when allowed to bypass the BNB by intraneural injection. Intraneural injection of fibrinogen, a clotting protein in plasma that was found to deposit in the nerve after nerve injury, also produced a decrease in mechanical thresholds when introduced into naive nerves. These results demonstrate that blood-borne molecules may play a role in the generation of neuropathic pain, suggesting that pain may be driven from infection or injury, at a distance from the nervous system. Furthermore, the breakdown of the BNB in neuropathic conditions was exploited to permit the entry of analgesic molecules that typically cannot pass the BNB, such as ProToxin-II, a BNB-impermeable Nav1.7 inhibitor. Therapeutics utilizing this mechanism could have selective access to injured nerves over healthy tissues.

Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain.

Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain.

Increased circulating rather than spinal cytokines accompany chronic pain behaviors in experimental bone cancer and arthritis

Neuroimmunology and Neuroinflammation is an open access journal, with focuses on neuroimmunology and neuroinflammation research, and coverage extending to other basic and clinical studies related to neuroscience.

66. Intrathecal administration of microRNA-124 alleviates both neuropathic pain and depression-like behavior in mice

MicroRNAs are short non-coding RNAs that regulate gene expression at the transcriptional as well as at the post-transcriptional level. Micro RNA 124 (miR124) is highly expressed in the central nervous system and keeps microglia in a quiescent state. Previously, we have shown that intrathecal administration of miR-124 reduced thermal hyperalgesia in response to peripheral inflammation. Here, we investigated whether miR124 can be used to treat neuropathic pain and comorbid depressive behavior. Intrathecal administration of miR124 starting at day 5 after spared nerve injury (SNI) in mice reversed the existing mechanical hyperalgesia. Depressive-like behavior was measured as increased immobility in a forced swim test. Intrathecal administration of miR124 inhibited this depressive-like behavior. The beneficial effect of miR124 treatment on SNI-induced pain and depressive behavior was associated with a decrease in the expression of the microglial activation marker IBA-1. Moreover, miR124 treatment induced an up regulation of the anti-inflammatory M2 microglial/macrophage marker CD206, while the expression of the pro-inflammatory M1 marker CD16/32 was down regulated in the spinal cord. Our findings indicate that miR124 treats both chronic pain and depressive-like behavior in the SNI model of chronic neuropathic pain by promoting the anti-inflammatory activity of spinal cord microglia/macrophages. Supported by NIH grants NS073939 and NS074999.

Addictive behaviors related to opioid use for chronic pain: A population-based study

The growing body of research showing increased opioid use in patients with chronic pain coupled with concerns regarding addiction encouraged the development of this population-based study. The goal of the study was to investigate the co-occurrence of indicators of addictive behaviors in patients with chronic non-cancer pain in long-term opioid treatment. The study combined data from the individual-based Danish Health Survey in 2010 and the official Danish health and socio-economic, individual-based registers. From a simple random sample of 25,000 adults (16 years or older) living in Denmark, 13,281 individuals were analyzed through multiple logistic regression analyses to assess the association between chronic pain (lasting ⩾6 months), opioid use, health behavior, and body mass index. Six potential addictive behaviors were identified: daily smoking; high alcohol intake; illicit drug use in the past year; obesity; long-term use of benzodiazepines; and long-term use of benzodiazepine-related drugs. At least 2 of the 6 addictive behaviors were observed in 22.6% of the long-term opioid users with chronic pain compared with 11.5% of the non-opioid users with chronic pain and 8.9% of the individuals without chronic pain. Thus, a strong association was demonstrated between long-term opioid use and the clustering of addictive behaviors. An intricate relationship between chronic pain, opioid use, and addictive behaviors was observed in this study, which deserves both clinical attention and further research.

AB1442-HPR Fear of movement in ankylosing spondilitis patients: A pilot study

BackgroundAnkylosing spondilitis (AS) is a chronic, inflammatory disorder characterized by pain and stiffness especially on back and sacroiliac joint. Pain, reduced spine mobility, and decreased physical functioning are the major...

Letter to the editor

So comparing an unvalidated instrument designed to measure lameness to the Canine Brief Pain Inventory, which has been validated to assess chronic pain, is like comparing apples and oranges. In the end, the most important thing to consider when choosing an outcome assessment instrument for a study is choosing a validated tool. The next step is choosing from amongst the validated tools the one that will allow the investigator to answer the question they are most interested in asking. If one wants to know whether an intervention decreases lameness, force plate gait analysis is an excellent choice. If one wants to know whether an intervention improves chronic pain behaviors during a dog's daily routine in its home environment, then the Canine BPI is a well validated option.

Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice

Chronic pancreatitis (CP) is a devastating disease characterized by persistent and uncontrolled abdominal pain. Our lack of understanding is partially due to the lack of experimental models that mimic the human disease and also to the lack of validated behavioral measures of visceral pain. The ligand-gated cation channel transient receptor potential ankyrin 1 (TRPA1) mediates inflammation and pain in early experimental pancreatitis. It is unknown if TRPA1 causes fibrosis and sustained pancreatic pain. We induced CP by injecting the chemical agent trinitrobenzene sulfonic acid (TNBS), which causes severe acute pancreatitis, into the pancreatic duct of C57BL/6 trpa1(+/+) and trpa1(-/-) mice. Chronic inflammatory changes and pain behaviors were assessed after 2-3 wk. TNBS injection caused marked pancreatic fibrosis with increased collagen-staining intensity, atrophy, fatty replacement, monocyte infiltration, and pancreatic stellate cell activation, and these changes were reflected by increased histological damage scores. TNBS-injected animals showed mechanical hypersensitivity during von Frey filament probing of the abdomen, decreased daily voluntary wheel-running activity, and increased immobility scores during open-field testing. Pancreatic TNBS also reduced the threshold to hindpaw withdrawal to von Frey filament probing, suggesting central sensitization. Inflammatory changes and pain indexes were significantly reduced in trpa1(-/-) mice. In conclusion, we have characterized in mice a model of CP that resembles the human condition, with marked histological changes and behavioral measures of pain. We have demonstrated, using novel and objective pain measurements, that TRPA1 mediates inflammation and visceral hypersensitivity in CP and could be a therapeutic target for the treatment of sustained inflammatory abdominal pain.

Perioperative Interventions to Reduce Chronic Postsurgical Pain

Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors-so called "preventative analgesia." In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan.

Enhanced GABAergic Activity in the Mouse Primary Somatosensory Cortex Is Insufficient to Alleviate Chronic Pain Behavior with Reduced Expression of Neuronal Potassium–Chloride Cotransporter

The correct balance between excitation and inhibition is crucial for brain function and disrupted in several pathological conditions. Excitatory neuronal circuits in the primary somatosensory cortex (S1) are modulated by local inhibitory neurons with the balance of this excitatory and inhibitory activity important for function. The activity of excitatory layer 2/3 neurons (L2/3) in the S1 cortex is increased in chronic pain, but it is not known how the local interneurons, nor the balance between excitation and inhibition, may change in chronic pain. Using in vivo two-photon calcium imaging and electrophysiology, we report here that the response of L2/3 local inhibitory neurons to both sensory stimulation and to layer 4 electrical stimulation increases in inflammatory chronic pain. Local application into L2/3 of a GABA(A) receptor blocker further enhanced the activity of S1 excitatory neurons and reduced pain thresholds, whereas local application of the GABA(A) receptor modulators (muscimol and diazepam) transiently alleviated the allodynia. This illustrates the importance of the local inhibitory pathways in chronic pain sensation. A reduction in the expression and function of the potassium-chloride cotransporter 2 occurred during chronic pain, which reduces the efficacy of the inhibitory inputs to L2/3 excitatory neurons. In summary, both excitatory and inhibitory neuronal activities in the S1 are enhanced in the chronic pain model, but the increased inhibition is insufficient to completely counterbalance the increased excitation and alleviate the symptoms of chronic pain.

A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development

BackgroundEvaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large animals are limited. To address this deficiency, we developed a neuropathic pain model in sheep, which shares many anatomical similarities in spine dimensions and cerebrospinal fluid volume as humans.MethodsA neuropathic pain state was induced in sheep by tight ligation and axotomy of the common peroneal nerve. The analgesic effect of intrathecal (IT) morphine was investigated. Interspecies comparison was conducted by analyzing the ceiling doses of IT morphine for humans, sheep, and rats.ResultsPeroneal nerve injury (PNI) produced an 86% decrease in von-Frey filament-evoked withdrawal threshold on postsurgery day 3 and the decrease lasted for the 8-week test period. Compared to the pre-injury, sham, and contralateral hindlimb, the IT morphine dose that produces 50% of maximum analgesia (ED50) for injured PNI hindlimb was 1.8-fold larger and Emax, the dose that produces maximal analgesia, was 6.1-fold lower. The sheep model closely predicts human IT morphine ceiling dose by allometric scaling. This is in contrast to the approximately 10-fold lower morphine ceiling dose predicted by the rat spinal nerve ligated or spared nerve injury models.ConclusionPNI sheep model has a fast onset and shows stable and long-lasting pain behavioral characteristics. Since the antinociceptive properties of IT morphine are similar to those observed in humans, the PNI sheep model will be a useful tool for the development of analgesics. Its large size and consistent chronic pain behavior will facilitate the development and evaluation of surgical intervention and gene therapy. The PNI sheep pain model provides us with the opportunity for multi-species testing, which will improve the success of clinical trials.

PI3K Contributed to Modulation of Spinal Nociceptive Information Related to ephrinBs/EphBs

There is accumulating evidence to implicate the importance of EphBs receptors and ephrinBs ligands were involved in modulation of spinal nociceptive information. However, the downstream mechanisms that control this process are not well understood. In the present study, we investigated whether phosphatidylinositol 3-kinase (PI3K), as the downstream effectors, participates in modulation of spinal nociceptive information related to ephrinBs/EphBs. Intrathecal injection of ephrinB1-Fc produced a dose- and time-dependent thermal and mechanical hyperalgesia, accompanied by the increase of spinal PI3K-p110γ, phosphorylation of AKT (p-AKT) and c-Fos expression. Pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented activation of spinal AKT induced by ephrinB1-Fc. Inhibition of spinal PI3K signaling dose-dependently prevented and reversed pain behaviors and spinal c-Fos protein expression induced by intrathecal injection of ephrinB1-Fc. Inhibition of EphBs receptors by intrathecal injection of EphB1-Fc reduced formalin-induced inflammation and chronic constrictive injury-induced neuropathic pain behaviors accompanied by decreased expression of spinal PI3K,p-AKT and c-Fos protein. Furthermore, pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented ephrinB1-Fc-induced ERK activation in spinal. These data demonstrated that PI3K and PI3K crosstalk to ERK signaling contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs.

Pain catastrophizing, threat, and the informational value of mood: Task persistence during a painful finger pressing task

Pain catastrophizing has shown to predict avoidance behavior in acute and chronic pain, but the literature is inconsistent. The present study tested the hypothesis that current mood and threat context moderate the relationship between pain catastrophizing and performance duration. Affective-motivational models postulate that negative and positive moods provide information about whether an activity is respectively threatening or safe. Moreover, it has been proposed that stable cognitive schemas about threat influence behavior particularly in threat-relevant contexts. The present study aimed to establish whether pain catastrophizing is related to less or greater performance duration, when participants experience respectively negative or positive moods, particularly in a high threatening pain context. A 2 mood×2 threat context between-subjects factorial design was applied in 89 healthy participants with pain catastrophizing as covariate and performance duration during a painful finger pressing task as dependent variables. As predicted, higher pain catastrophizing was associated with less performance duration when participants experienced negative moods. The opposite was found when participants experienced positive moods. Moreover, these relationships were most pronounced in a high threatening pain context. This study suggests that the relationship between pain catastrophizing and performance duration during painful activities is moderated by situational factors such as current mood and threat context.

Factors That Affect Functional Capacity in Patients With Musculoskeletal Pain: A Delphi Study Among Scientists, Clinicians, and Patients

Lakke SE, Wittink H, Geertzen JH, van der Schans CP, Reneman MF. Factors that affect functional capacity in patients with musculoskeletal pain: a Delphi study among scientists, clinicians, and patients. ObjectiveTo reach consensus on the most important biopsychosocial factors that influence functional capacity results in patients with chronic nonspecific musculoskeletal pain, arranged in the framework of the International Classification of Functioning, Disability and Health. DesignThree-round, internet-based Delphi survey. SettingNot applicable. ParticipantsParticipants were scientists, clinicians, and patients familiar with functional capacity testing. Scientists were invited through purposive sampling based on the number of relevant publications in peer-reviewed journals. The scientists recruited clinicians and patients through snowball sampling. InterventionsNot applicable. Main Outcome MeasuresConsensus was reached if at least moderate influence (25%) was achieved and an interquartile range of no more than 1 point was reached. ResultsThirty-three scientists, 21 clinicians, and 21 patients from 9 countries participated. Participants reached consensus on 6 factors that can influence the outcome of the lifting test, having a median of severe influence (50%–95%): catastrophic thoughts and fear, patient adherence to “doctor's orders,” internal and external motivation, muscle power, chronic pain behavior, and avoidance behavior. Motivation, chronic pain behavior, and sensation of pain were the top 3 factors affecting postural tolerance and repetitive movement functional capacity tests. Furthermore, participants reported 28 factors having a median of moderate influence (25%–49%) that could influence the outcome of lifting, postural tolerance, and repetitive movement tests. ConclusionsOverall, chronic pain behavior, motivation, and sensation of pain are the main factors that can influence functional capacity results. We recommend that scientists and clinicians, respectively, consider the most important factors when planning future studies and when interpreting functional capacity test results.

Perceptions of shared decision making and decision aids among rural primary care clinicians.

Shared decision making (SDM) and decision aids (DAs) increase patients' involvement in health care decisions and enhance satisfaction with their choices. Studies of SDM and DAs have primarily occurred in academic centers and large health systems, but most primary care is delivered in smaller practices, and over 20% of Americans live in rural areas, where poverty, disease prevalence, and limited access to care may increase the need for SDM and DAs. To explore perceptions and practices of rural primary care clinicians regarding SDM and DAs. Cross-sectional survey. Setting and Participants Primary care clinicians affiliated with the Oregon Rural Practice-based Research Network. Surveys were returned by 181 of 231 eligible participants (78%); 174 could be analyzed. Two-thirds of participants were physicians, 84% practiced family medicine, and 55% were male. Sixty-five percent of respondents were unfamiliar with the term shared decision making, but following definition, 97% reported that they found the approach useful for conditions with multiple treatment options. Over 90% of clinicians perceived helping patients make decisions regarding chronic pain and health behavior change as moderate/hard in difficulty. Although 69% of respondents preferred that patients play an equal role in making decisions, they estimate that this happens only 35% of the time. Time was reported as the largest barrier to engaging in SDM (63%). Respondents were receptive to using DAs to facilitate SDM in print- (95%) or web-based formats (72%), and topic preference varied by clinician specialty and decision difficulty. Rural clinicians recognized the value of SDM and were receptive to using DAs in multiple formats. Integration of DAs to facilitate SDM in routine patient care may require addressing practice operation and reimbursement.

Intracerebroventricular 4-methylcatechol (4-MC) ameliorates chronic pain associated with depression-like behavior via induction of brain-derived neurotrophic factor (BDNF).

Neuropathic pain concurrent with mood disorder from peripheral nerve injury is a serious clinical problem that significantly affects quality of life. Recent studies have suggested that a lack of brain-derived neurotrophic factor (BDNF) in the limbic system may cause this pain-emotion. BDNF is induced in cultured neurons by 4-methylcatechol (4-MC), but the role of 4-MC-induced BDNF in pain-emotion is poorly understood. Thus, we assessed the possible involvement of BDNF in brain in depression-like behavior during chronic pain following peripheral nerve injury. In addition, we examined whether intracerebroventricular (i.c.v.) 4-MC prevents chronic pain in rats and produces an antidepressant effect. Sprague-Dawley rats implanted intracerebroventricularly with a PE-10 tube were subjected to chronic constriction injury (CCI). Pain was assessed by a reduction in paw withdrawal latency (PWL) to heat stimuli after CCI. We also used a forced swimming testing (FST; time of immobility, in seconds) from day 14 to day 21 after CCI. Modulation of pain and emotional behavior was performed by injection of PD0325901 (a MEK1/2 inhibitor). 4-MC (100 nM) was continuously administered i.c.v. for 3 days during the period from day 14 to day 21 after CCI. To block analgesic and antidepressant effects, anti-BDNF antibody or K252a (a TrkB receptor inhibitor) was injected in combination with 4-MC. Naloxone was also coadministered to confirm the analgesic effect of 4-MC. During the chronic stage after CCI, the rats showed a sustained decrease in PWL (thermal hyperalgesia) associated with extension of the time of immobility (depression-like behavior). PD0325901 significantly reduced the decrease in PWL and the increased time of immobility after CCI. The decreased PWL and increased time of immobility were also reduced by 4-MC and by treatment with an ERK1/2 inhibitor. These effects of 4-MC i.c.v. were reversed by anti-BDNF and K252a. The analgesic effect of 4-MC i.c.v. was also antagonized by naloxone. Based on these results, we suggest that a lack of BDNF and activation of ERK1/2 in the pain-emotion network in the CNS may be involved in depression-like behavior during chronic pain. 4-MC i.c.v. ameliorates chronic pain and depression-like behavior by producing of BDNF and normalization of ERK1/2 activation. Therefore, enhancement of BDNF may be a new treatment strategy for chronic pain associated with depression.

Mechanical allodynia generated by stimulation of unmyelinated afferent nerve fibres

Mechanical allodynia generated by stimulation of unmyelinated afferent nerve fibres

Inter-regional remodeling between the primary somatosensory cortex and anterior cingulate cortex accelerates chronic pain behavior

Previous archaeometallurgical studies on Bronze Age China mainly focused on finished artefacts, whereas our understanding of copper smelting technology of this period is still limited. This paper, for the first time, presents analytical results of metal production remains from the site of Laoniupo in Guanzhong Plain, central Shaanxi. It reveals that arsenical copper was produced at this site by smelting arsenic-rich polymetallic ores with raw copper or high purity copper ores. The identification of metal production in the Guanzhong Plain is significant for the investigation of regional development and inter-regional interaction of Bronze Age cultures in China. The possible exploitation of ores from deposits in the Qinling Mountain region during this period is also discussed in this article.

Intersection of chronic pain treatment and opioid analgesic misuse: causes, treatments, and policy strategies.

Treating chronic pain in the context of opioid misuse can be very challenging. This paper explores the epidemiology and potential treatments for chronic pain and opioid misuse and identifies educational and regulation changes that may reduce diversion of opioid analgesics. We cover the epidemiology of chronic pain and aberrant opioid behaviors, psychosocial influences on pain, pharmacological treatments, psychological treatments, and social treatments, as well as educational and regulatory efforts being made to reduce the diversion of prescription opioids. There are a number of ongoing challenges in treating chronic pain and opioid misuse, and more research is needed to provide strong, integrated, and empirically validated treatments to reduce opioid misuse in the context of chronic pain.

Inter-regional Contribution of Enhanced Activity of the Primary Somatosensory Cortex to the Anterior Cingulate Cortex Accelerates Chronic Pain Behavior

Multiple cortical areas are involved in pain processing, including the primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC). Although accumulations of evidence suggest that the S1 activity increases under chronic pain conditions, whether plastic change occurs or not within the S1, and whether and how the plastic change contributes to chronic pain behavior, is unknown. Here, we provide the first evidence that intra-regional remodeling within the mouse S1 accelerates chronic pain behavior by modulating neuronal activity in the ACC, one of the important cortical areas for chronic pain. Using two-photon Ca(2+) imaging, we found that the spontaneous activity of layer 2/3 neurons in the S1 and then response to sensory and layer 4 stimulations increased under chronic pain conditions. In addition, pharmacological attenuation and facilitation of S1 activity attenuated and facilitated the chronic pain behavior, respectively. Furthermore, electrical response of the ACC to peripheral stimulation successfully correlated with S1 neuronal activity, and inhibition of ACC activity alleviated the mechanical allodynia. The present results will provide development of efficient therapeutic strategies against chronic pain by focusing on the S1 and ACC.