The Effect of Everyday-Life Social Contact on Pain.

Pain is a biopsychosocial phenomenon, resulting from the interplay between physiological and psychological processes and social factors. Given that humans constantly interact with others, the effect of social factors is particularly relevant. Documenting the significance of the social modulation of pain, an increasing number of studies have investigated the effect of social contact on subjective pain intensity and pain-related physiological changes. While evidence suggests that social contact can alleviate pain, contradictory findings indicate an increase in pain intensity and a deterioration of pain coping strategies. This evidence primarily stems from studies examining the effect of social contact on pain within highly controlled laboratory conditions. Moreover, pain assessments often rely on one-time subjective reports of average pain intensity across a predefined period. Ecological momentary assessments (EMAs) can circumvent these problems, as they can capture diverse aspects of behavior and experiences multiple times a day, in real time, with high resolution, and within naturalistic and ecologically valid settings. These multiple measures allow for the examination of fluctuations of pain symptoms throughout the day in relation to affective, cognitive, behavioral, and social factors. In this opinion paper, we review the current state and future relevance of EMA-based social pain research in daily life. Specifically, we examine whether everyday-life social support reduces or enhances pain. The first part of the paper provides a comprehensive overview of the use of EMA in pain research and summarizes the main findings. The review of the relatively limited number of existing EMA studies shows that the association between pain and social contact in everyday life depends on numerous factors, including pain syndromes, temporal dynamics, the nature of social interactions, and characteristics of the interaction partners. In line with laboratory research, there is evidence that everyday-life social contact can alleviate, but also intensify pain, depending on the type of social support. Everyday-life emotional support seems to reduce pain, while extensive solicitous support was found to have opposite effects. Moreover, positive short-term effects of social support can be overshadowed by other symptoms such as fatigue. Overall, gathering and integrating experiences from a patient's social environment can offer valuable insights. These insights can help interpret dynamics in pain intensity and accompanying symptoms such as depression or fatigue. We conclude that factors determining the reducing versus enhancing effects of social contact on pain need to be investigated more thoroughly. We advocate EMA as the assessment method of the future and highlight open questions that should be addressed in future EMA studies on pain and the potential of ecological momentary interventions for pain treatment.

A Novel Approach for the Control of Inflammatory Pain: Prostaglandin E2 Complexation by Randomly Methylated ß-Cyclodextrins.

BACKGROUND: Inhibitors of cyclooxygenase, which block the formation of prostaglandin (PG) E2, are the standard treatment of inflammatory pain. These drugs, however, have serious gastrointestinal, renal, and cardiovascular side effects that limit their clinical use. Cyclodextrins are neutral glucose oligomers that form a hydrophilic outer and a hydrophobic interior cavity used to carry hydrophilic substances. Methyl-ß-cyclodextrins are used currently in several drugs as enhancers and also to deliver PGs. We therefore hypothesized that randomly methylated ß-cyclodextrins (RAMEB) could be used for pain treatment. METHODS: An in silico screening for important inflammatory mediators (eg, PGE2, substance P, bradykinin, and calcitonin gene-related peptide) was performed to predict the probability of these molecules binding to RAMEB. Thereafter, a comprehensive in vitro study investigated the complexation affinity of the best target toward RAMEB or its RAMEB-fraction L (FL) using capillary electrophoresis.Wistar rats were injected intraplantarly with complete Freund's adjuvant (CFA) for 96 hours to induce inflammatory hyperalgesia. Subsequently, rats were treated intraplantarly or intravenously either with RAMEB or RAMEB FL and compared with the respective controls. Parecoxib was used as positive control. Mechanical (paw pressure threshold, PPT) and thermal (paw withdrawal latency) nociceptive thresholds were determined before injection and at the indicated time points thereafter. Paw tissue was collected after treatments, and PGE2 and PGD2 contents were measured. Analysis of variance was used for data analysis followed by appropriate post hoc comparisons. RESULTS: In silico screening indicated that PGE2, with the highest affinity, was the best candidate for RAMEB binding. Likewise, in capillary electrophoresis experiments, RAMEB had a high affinity to form inclusion complexes with the PGE2 (stability constant [K], 360 1/M; 95% confidence interval [C]: 347.58-372.42 M). Local treatment with RAMEB alleviated CFA-induced mechanical (PPT: 76.25 g; 95% CI: 56.24-96.25 g) and thermal hyperalgesia (PPT: 8.50 seconds; 95% CI: 6.76-10.23 seconds). Moreover, a systemic administration of RAMEB decreased CFA-induced mechanical (PPT: 126.66 g; 95% CI: 114.54-138.77 g) and thermal hyperalgesia (paw withdrawal latency: 11.47 seconds; 95% CI: 9.26-13.68 seconds). RAMEB FL resulted in greater in vitro PGE2-binding capacity and decreased PG content as well as hyperalgesia in vivo to a similar extent. Motor activity of the rats was not altered by RAMEB or RAMEB FL. CONCLUSIONS: Capture of PGs by cyclodextrins could be a novel and innovative tool for the treatment of inflammatory pain and bypassing some unwanted side effects of cyclooxygenase inhibitors.

Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy.

Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage. KEY MESSAGES: • In diabetic painful neuropathy in rats: • Blood nerve barrier and blood DRG barrier are leaky for micromolecules. • Perineurial Cldn1 sealing the blood nerve barrier is specifically downregulated. • Endoneurial vessel-associated macrophages are also decreased. • These changes occur after onset of hyperalgesia thereby maintaining rather than inducing pain.

Clinical phenotypes and classification algorithm for complex regional pain syndrome.

OBJECTIVE: We pursued the hypothesis that complex regional pain syndrome (CRPS) signs observed by neurologic examination display a structure allowing for alignment of patients to particular phenotype clusters. METHODS: Clinical examination data were obtained from 3 independent samples of 444, 391, and 202 patients with CRPS. The structure among CRPS signs was analyzed in sample 1 and validated with sample 2 using hierarchical clustering. For patients with CRPS in sample 3, an individual phenotype score was submitted to k-means clustering. Pain characteristics, quantitative sensory testing, and psychological data were tested in this sample as descriptors for phenotypes. RESULTS: A 2-cluster structure emerged in sample 1 and was replicated in sample 2. Cluster 1 comprised minor injury eliciting CRPS, motor signs, allodynia, and glove/stocking-like sensory deficits, resembling a CRPS phenotype most likely reflecting a CNS pathophysiology (the central phenotype). Cluster 2, which consisted of edema, skin color changes, skin temperature changes, sweating, and trophic changes, probably represents peripheral inflammation, the peripheral phenotype. In sample 3, individual phenotype scores were calculated as the sum of the mean values of signs from each cluster, where signs from cluster 1 were coded with 1 and from cluster 2 with -1. A k-means algorithm separated groups with 78, 36, and 88 members resembling the peripheral, central, and mixed phenotypes, respectively. The central phenotype was characterized by cold hyperalgesia at the affected limb. CONCLUSIONS: Statistically determined CRPS phenotypes may reflect major pathophysiologic mechanisms of peripheral inflammation and central reorganization.

The connection of monocytes and reactive oxygen species in pain.

The interplay of specific leukocyte subpopulations, resident cells and proalgesic mediators results in pain in inflammation. Proalgesic mediators like reactive oxygen species (ROS) and downstream products elicit pain by stimulation of transient receptor potential (TRP) channels. The contribution of leukocyte subpopulations however is less clear. Local injection of neutrophilic chemokines elicits neutrophil recruitment but no hyperalgesia in rats. In meta-analyses the monocytic chemoattractant, CCL2 (monocyte chemoattractant protein-1; MCP-1), was identified as an important factor in the pathophysiology of human and animal pain. In this study, intraplantar injection of CCL2 elicited thermal and mechanical pain in Wistar but not in Dark Agouti (DA) rats, which lack p47(phox), a part of the NADPH oxidase complex. Inflammatory hyperalgesia after complete Freund's adjuvant (CFA) as well as capsaicin-induced hyperalgesia and capsaicin-induced current flow in dorsal root ganglion neurons in DA were comparable to Wistar rats. Macrophages from DA expressed lower levels of CCR2 and thereby migrated less towards CCL2 and formed limited amounts of ROS in vitro and 4-hydroxynonenal (4-HNE) in the tissue in response to CCL2 compared to Wistar rats. Local adoptive transfer of peritoneal macrophages from Wistar but not from DA rats reconstituted CCL2-triggered hyperalgesia in leukocyte-depleted DA and Wistar rats. A pharmacological stimulator of ROS production (phytol) restored CCL2-induced hyperalgesia in vivo in DA rats. In Wistar rats, CCL2-induced hyperalgesia was completely blocked by superoxide dismutase (SOD), catalase or tempol. Likewise, inhibition of NADPH oxidase by apocynin reduced CCL2-elicited hyperalgesia but not CFA-induced inflammatory hyperalgesia. In summary, we provide a link between CCL2, CCR2 expression on macrophages, NADPH oxidase, ROS and the development CCL2-triggered hyperalgesia, which is different from CFA-induced hyperalgesia. The study further supports the impact of CCL2 and ROS as potential targets in pain therapy.