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Placebo effects influence symptom perceptions and treatment outcomes. Placebo effects can be explored in laboratory settings controlling for natural history and expectations. Such a mechanistic approach to neurological disorders has been implemented in the domain of chronic clinical pain and other neurological disorders. This article therefore focuses on definitions and historical notes related to placebo effects and mechanisms of placebo effects in chronic pain. Knowledge on mechanisms of placebo effects could inform current clinical practice for the treatment of neurological disorders by focusing on patients (and providers) expectations for outcome optimization.
Peripheral inflammatory hyperalgesia depends on the sensitization of primary nociceptive neurons. Inflammation drives molecular alterations not only locally but also in the dorsal root ganglion (DRG) where interleukin-1 beta (IL-1β) and purinoceptors are upregulated. Activation of the P2X7 purinoceptors by ATP is essential for IL-1β maturation and release. At the DRG, P2X7R are expressed by satellite glial cells (SGCs) surrounding sensory neurons soma. Although SGCs have no projections outside the sensory ganglia these cells affect pain signaling through intercellular communication. Therefore, here we investigated whether activation of P2X7R by ATP and the subsequent release of IL-1β in DRG participate in peripheral inflammatory hyperalgesia. Immunofluorescent images confirmed the expression of P2X7R and IL-1β in SGCs of the DRG. The function of P2X7R was then verified using a selective antagonist, A-740003, or antisense for P2X7R administered in the L5-DRG. Inflammation was induced by CFA, carrageenan, IL-1β, or PGE administered in rat's hind paw. Blockage of P2X7R at the DRG reduced the mechanical hyperalgesia induced by CFA, and prevented the mechanical hyperalgesia induced by carrageenan or IL-1β, but not PGE. It was also found an increase in P2X7 mRNA expression at the DRG after peripheral inflammation. IL-1β production was also increased by inflammatory stimuli and , using SGC-enriched cultures stimulated with LPS. In LPS-stimulated cultures, activation of P2X7R by BzATP induced the release of IL-1β, which was blocked by A-740003. In summary, our data suggest that peripheral inflammation leads to the activation of P2X7R expressed by SGCs at the DRG. Then, ATP-induced activation of P2X7R mediates the release of IL-1β from SGC. This evidence places the SGC as an active player in the establishment of peripheral inflammatory hyperalgesia and highlights the importance of the events in DRG for the treatment of inflammatory diseases.
Temporomandibular joint disorder (TMD) is associated with pain in the joint (temporomandibular joint, TMJ) and muscles involved in mastication. TMD pain dissipates following menopause but returns in some women undergoing estrogen replacement therapy. Progesterone has both anti-inflammatory and antinociceptive properties, while estrogen's effects on nociception are variable and highly dependent on both natural hormone fluctuations and estrogen dosage during pharmacological treatments, with high doses increasing pain. Allopregnanolone, a progesterone metabolite and positive allosteric modulator of the GABA receptor, also has antinociceptive properties. While progesterone and allopregnanolone are antinociceptive, their effect on estrogen-exacerbated TMD pain has not been determined. We hypothesized that removing the source of endogenous ovarian hormones would reduce inflammatory allodynia in the TMJ of rats and both progesterone and allopregnanolone would attenuate the estrogen-provoked return of allodynia. Baseline mechanical sensitivity was measured in female Sprague-Dawley rats (150-175 g) using the von Frey filament method followed by a unilateral injection of complete Freund's adjuvant (CFA) into the TMJ. Mechanical allodynia was confirmed 24 h later; then rats were ovariectomized or received sham surgery. Two weeks later, allodynia was reassessed and rats received one of the following subcutaneous hormone treatments over 5 days: a daily pharmacological dose of estradiol benzoate (E2; 50 μg/kg), daily E2 and pharmacological to sub-physiological doses of progesterone (P4; 16 mg/kg, 16 μg/kg, or 16 ng/kg), E2 daily and interrupted P4 given every other day, daily P4, or daily vehicle control. A separate group of animals received allopregnanolone (0.16 mg/kg) instead of P4. Allodynia was reassessed 1 h following injections. Here, we report that CFA-evoked mechanical allodynia was attenuated following ovariectomy and daily high E2 treatment triggered the return of allodynia, which was rapidly attenuated when P4 was also administered either daily or every other day. Allopregnanolone treatment, whether daily or every other day, also attenuated estrogen-exacerbated allodynia within 1 h of treatment, but only on the first treatment day. These data indicate that when gonadal hormone levels have diminished, treatment with a lower dose of progesterone may be effective at rapidly reducing the estrogen-evoked recurrence of inflammatory mechanical allodynia in the TMJ.
Low back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies. Spinal mobilization (SM) is a non-pharmacological approach recommended by most clinical guidelines for LBP, but greater utilization and treatment optimization are hampered by a lack of mechanistic knowledge underlying its hypoalgesic clinical effects.
This study aims to explore the value of serum galectin-3 in patients with herpes zoster neuralgia (HZN) and postherpetic neuralgia (PHN) and other factors influencing HZN and PHN occurrence. Samples from forty patients with herpes zoster neuralgia (HZN) (Group H), 40 patients with nonherpes zoster neuralgia (Group N), and 20 cases of health check-up were collected. Patients were divided into PHN group (Group A) and non-PHN group (Group B) according to the occurrence of PHN in Group H. Galectin-3, T-lymphocyte subsets, and IL-6 were recorded in all patients. The changes of galectin-3 in patients with early HZN and PHN were analyzed by single-factor analysis and multifactor analysis. The age (=0.012) and NRS scores ( < 0.001) of PHN patients were significantly higher than those of non-PHN patients and other neuralgia patients. The ratio of CD3+ ( = 80.336, < 0.001), CD4+ ( = 12.459, < 0.001) lymphocyte subsets, and CD4+/CD8+ ( = 15.311, < 0.001) decreased significantly in PHN patients. The level of blood IL-6 ( = 139.446, < 0.001) in PHN patients was significantly increased. Serum galectin-3 was significantly higher in HZN patients than in PHN patients ( < 0.05); IL-6 (OR = 10.002, 95% CI: 3.313-30.196, < 0.001) and galectin-3 (OR = 3.719, 95% CI: 1.261-10.966, =0.017) were the risk factors for HZN; galectin-3 (OR = 17.646, 95% CI: 2.795-111.428, =0.002) was also the risk factor for PHN. ROC curve analysis also showed that serum galectin-3 was a better predictor of poor prognosis (AUC = 0.934, < 0.001). Therefore, as an independent risk factor of HZN and PHN, serum galectin-3 may be used as a new biochemical marker in clinical practice.
Resident microglia of the central nervous system are being increasingly recognized as key players in diseases such as neuropathic pain. Biochemical and behavioral studies in neuropathic pain rodent models have documented compelling evidence of the critical role of ATP mediated-P2X4R-brain-derived neurotrophic factor (BDNF) signaling pathway in the initiation and maintenance of pain hypersensitivity, a feature driving neuropathic pain-related behavior. The goal of this study was to develop and characterize an in vitro cell line model of activated microglia that can be subsequently utilized for screening neuropathic pain therapeutics. In the present study, we characterized the SIM-A9 microglia cell line for key molecules in the P2X4R-BDNF signaling axis using a combination of biochemical techniques and developed an ATP-activated SIM-A9 microglia model. We present three novel findings: first, SIM-A9 cells expressed P2X4R and BDNF proteins, second, ATP, but not LPS, was cytocompatible with SIM-A9 cells and third, exposure of cells to optimized ATP concentrations for defined periods increased intracellular expression of Iba1 and BDNF proteins. Increased Iba1 levels confirmed microglia activation and increased BDNF expression confirmed ATP-mediated stimulation of the P2X4R signaling pathway. We propose that this ATP-activated SIM-A9 cell line model system can be utilized for screening both small- as well as macro-molecular neuropathic pain therapeutics targeting BDNF and/or P2X4R knockdown.
There is a strong relationship between palatable diet and pain sensitivity, and the cannabinoid and opioid systems might play an important role in this correlation. The palatable diet used in many animal models of obesity is the cafeteria (CAF) diet, based on human food with high sugar, salt, and fat content. In this study, we investigated whether long-term exposure to a CAF diet could modify pain sensitivity and explored the role of the cannabinergic system in this modification. Male Sprague-Dawley rats were divided into two groups: one fed with standard chow only (CO) and the other with extended access (EA) to a CAF diet. Hot plate and tail flick tests were used to evaluate pain sensitivity. At the end of a 40-day CAF exposure, EA rats showed a significant increase in the pain threshold compared to CO rats, finding probably due to up-regulation of CB1 and mu-opioid receptors. Instead, during abstinence from palatable foods, EA animals showed a significant increase in pain sensibility, which was ameliorated by repeated treatment with a fatty acid amide hydrolase inhibitor, PF-3845 (10 mg/kg, intraperitoneally), every other day for 28 days. analysis of the brains of these rats clearly showed that this effect was mediated by mu-opioid receptors, which were up-regulated following repeated treatment of PF-3845. Our data add to the knowledge about changes in pain perception in obese subjects, revealing a key role of CB1 and mu-opioid receptors and their possible pharmacological crosstalk and reinforcing the need to consider this modulation in planning effective pain management for obese patients.
Acute pain trajectories are associated with long-term outcomes such as persistent pain and functional disability in adults. However, there are limited data on acute postoperative pain trajectories in the pediatric population. The aims of this study were to investigate acute postoperative pain trajectories, their predictors, and their impact on long- term outcomes in adolescents with idiopathic scoliosis.
Successfully predicting the susceptibility of individuals to placebo analgesics will aid in developing more effective pain medication and therapies, as well as aiding potential future clinical use of placebos. In pursuit of this goal, we analyzed healthy and chronic pain patients' patterns of responsiveness during conditioning rounds and their links to conditioned placebo analgesia and the mediating effect of expectation on those responses. We recruited 579 participants (380 healthy, 199 with temporomandibular disorder [TMD]) to participate in a laboratory placebo experiment. Individual pain sensitivity dictated the temperatures used for high- and low-pain stimuli, paired with red or green screens, respectively, and participants were told there would be an analgesic intervention paired with the green screens. Over two conditioning sessions and one testing session, participants rated the painfulness of each stimulus on a visual analogue scale from 0 to 100. During the testing phase, the same temperature was used for both red and green screens to assess responses to the placebo effect, which was defined as the difference between the average of the high-pain-cue stimuli and low-pain-cue stimuli. Delta scores, defined as each low-pain rating subtracted from its corresponding high-pain rating, served as a means of modeling patterns of conditioning strength and placebo responsiveness. Latent class analysis (LCA) was then conducted to classify the participants based on the trajectories of the delta values during the conditioning rounds. Classes characterized by persistently greater or increasing delta scores during conditioning displayed greater placebo analgesia during testing than those with persistently lower or decreasing delta scores. Furthermore, the identified groups' expectation of pain relief acted as a mediator for individual placebo analgesic effects. This study is the first to use LCA to discern the relationship between patterns of learning and the resultant placebo analgesia in chronic pain patients. In clinical settings, this knowledge can be used to enhance clinical pain outcomes, as chronic pain patients with greater prior experiences of pain reduction may benefit more from placebo analgesia.
The current UK vaccination programme for herpes zoster (HZ) excludes people aged ≥80 years. This study aimed to quantify the number of individuals ≥80 years who missed HZ vaccination and the consequent epidemiological and economic burden of HZ and post-herpetic neuralgia (PHN).