The Effect of Stress on Repeated Painful Stimuli with and Without Painful Conditioning.

OBJECTIVES: Stress and pain have been interrelated in clinical widespread pain conditions. Studies indicate that acute experimental stress in healthy volunteers has a negative effect on the descending inhibitory pain control system and thus the ability to inhibit one painful stimulus with another (conditioned pain modulation [CPM]) although without effect on general pain sensitivity. CPM effects can be assessed immediately after the stress induction, whereas some physiological stress responses (e.g., cortisol release) are delayed and longer lasting. It is unclear whether CPM may relate to stress-induced increases in cortisol. DESIGN: Twenty-five healthy men had CPM effects measured over a period of 10 minutes. Pain detection thresholds (PDTs) were assessed by repeated test stimuli with cuff algometry on one leg, with and without painful cuff pressure conditioning on the contralateral leg. CPM effects, assessed as the increase in PDT during conditioning stimulation compared with without, were measured before and after experimental stress and a control condition (Montreal Imaging Stress Task [MIST]). Saliva cortisol levels and self-perceived stress were collected. RESULTS: Participants reported the MIST to be more stressful compared with the MIST control, but cortisol levels did not change significantly from baseline. In all sessions, PDT increased during conditioning (P = 0.001), although the MIST compared with the MIST control had no significant effect on PDT or CPM effects. A negative correlation between changes in cortisol and conditioned PDT was found when applying the MIST (P < 0.03). CONCLUSIONS: No significant effect of stress was found on CPM compared with a matched control condition. Individual changes in experimental stress and in conditioned pain sensitivity may be linked with cortisol.

A human surrogate model of itch utilizing the TRPA1 agonist trans-cinnamaldehyde.

The thermoreceptive transient receptor potential ankyrin 1 (TRPA1) is important in the transmission of itch, and its agonist trans-cinnamaldehyde has occasionally been reported to be a pruritogen in humans. However, no studies have accurately quantified the capabilities of trans-cinnamaldehyde to induce itch and related dysesthetic sensations. The present study examined alterations in somatosensory and vasomotor parameters in response to topical trans-cinnamaldehyde 5% and vehicle (ethanol) in 24 healthy subjects. During the study the following parameters were recorded: itch area and intensity, hyperknesis, alloknesis, neurogenic flare, skin blood flow and temperature. Trans-cinnamaldehyde evoked moderate itch sensation, flare, hyperknesis and alloknesis (p < 0.001). Blood flow and skin temperature were elevated in the area of trans-cinnamaldehyde application (p < 0.001). Significant positive correlations were found between blood flow and skin temperature, itch area and blood flow, and itch area and skin temperature. Topical trans-cinnamaldehyde proved feasible as a human itch model with applicability in studying itch mechanisms or anti-pruritic drug profiling.

Cold and L-menthol-induced sensitization in healthy volunteers--a cold hypersensitivity analogue to the heat/capsaicin model.

Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 ± 0.6 years). Cold stimulation of 5°C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P < 0.001). L-menthol evoked secondary hyperalgesia to pinprick (P < 0.001) particularly in females (P < 0.05) and also induced secondary allodynia to von Frey and brush (P < 0.001). Application of cold stimuli kept these areas enlarged with a higher response in females to brush after the third cold cycle (P < 0.05). Skin blood flow increased after L-menthol (P < 0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity.

Primary culture of trigeminal satellite glial cells: a cell-based platform to study morphology and function of peripheral glia.

Primary cell culture provides an experimental platform in which morphology, physiology, and cell-cell communication pathways can be studied under a well-controlled environment. Primary cell cultures of peripheral and central glia offer unique possibilities to clarify responses and pathways to different stimuli. Peripheral glia, satellite glial cells (SGCs), which surround neuronal cell bodies within sensory ganglia, have recently been known as key players in inflammation and neuronal sensitization. The objectives of this study were 1) to establish a cell-based platform of cultured trigeminal SGCs to study glial marker expression and functions under control conditions; 2) to validate the cell-based platform by prostaglandin E2 (PGE2) release response following administration of Cisplatin; and 3) to investigate inhibition of PGE2 release by glial modulators, Ibudilast and SKF86002. Primary cell cultures of SGCs from rat trigeminal ganglia were established following enzymatically and mechanically dissociation of the ganglia. Cultures were characterized in vitro for up to 21 days post isolation for morphological and immunocytochemical characteristics. PGE2 release, determined by ELISA, was used as a pro-inflammatory marker to characterize SGCs response to chemotherapeutic agent, Cisplatin, known to contribute in chemotherapy-induced peripheral neuropathy. Our results indicate that 1) isolated SGCs maintained their characteristics in vitro for up to 21 days; 2) Cisplatin enhanced PGE2 release from the SGCs, which was attenuated by Ibudilast and SKF86002. These findings confirm the utility and validity of the cultured trigeminal SGCs platform for glial activation and modulation; and suggest further investigation on Ibudilast and SKF86002 in prevention of chemotherapy-induced pain.