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Delivery of behavioral health interventions on the internet offers many benefits, including accessibility, cost-effectiveness, convenience, and anonymity. In recent years, an increased number of internet interventions have been developed, targeting a range of conditions and behaviors, including depression, pain, anxiety, sleep disturbance, and eating disorders. Human support (coaching) is a common component of internet interventions that is intended to boost engagement; however, little is known about how participants interact with coaches and how this may relate to their experience with the intervention. By examining the data that participants produce during an intervention, we can characterize their interaction patterns and refine treatments to address different needs.
Learn More >Bidirectional selection of mice for high (HA) and low (LA) swim stress-induced analgesia (SSIA) is associated with a divergent response to opioids. In the current study, we investigated whether the genetic divergence in opioid system activity between HA and LA mice also affects cannabinoid sensitivity. Additionally, we also investigated whether the endocannabinoid system mediates SSIA in these lines. Numerous reports support the existence of pharmacological and molecular interactions between the opioid and cannabinoid systems along the pain pathways, as both systems utilize the same G-protein subtype for signal transduction. Mice from both lines were treated with a non-selective CB/CB agonist, WIN55,212-2 and their behavior was evaluated according to the tetrad paradigm assessing antinociception, catalepsy, hypothermia and locomotor activity. Surprisingly, the engagement of CB receptors in SSIA was not confirmed. G-protein activation was studied in different brain regions and the spinal cord in the [S]GTPγS assay. It was shown that WIN55,212-2 produced more potent antinociception in HA than in LA mice. Also, HA mice displayed stronger cannabinoid-induced catalepsy in the bar test. However, LA mice were more sensitive to the hypothermic effect of WIN55,212-2. The intensity of behavioral responses to WIN55,212-2 was correlated with increased G-protein activation in the periaqueductal gray matter, frontal cortex, striatum and thalamus in HA mice. A weak response to WIN55,212-2 in LA mice could depend on impaired CB receptor signaling. In conclusion, differences in both opioid and cannabinoid sensitivity between HA and LA mice could stem from alterations in intracellular second messenger mechanisms involving G-protein activation.
Learn More >Reduced blood flow in the skin is observed in patients with neuropathic pain and in animal models. The aim of the present study was to elucidate the relationship between reduced skin blood flow and neuropathic pain in mice with a chronic constriction injury (CCI). Noradrenaline-induced contraction was enhanced in isolated plantar arteries ipsilateral to the CCI surgery compared to the contralateral arteries. Ten μM hydralazine, a peripheral vasodilator, at improved the enhanced contractile response in the ipsilateral arteries. The plantar blood flow in vivo was lower on the ipsilateral side of the CCI mice than on the contralateral side, and a 50% paw withdrawal threshold, as measured using the von Frey filament test, was lower on the former than on the latter side. An intraperitoneal injection (i.p.) of hydralazine (1 mg/kg) or phentolamine (5 mg/kg) improved blood flow in the skin and hyperalgesia in the ipsilateral plantar. In adrenalectomized CCI mice, plantar blood flow in the skin on the ipsilateral side was increased compared to in sham-operated mice, which was accompanied by alleviation of hyperalgesia. Moreover, the enhanced contractile response to noradrenaline was also observed in the ipsilateral plantar arteries isolated from the adrenalectomized CCI mice. Either hydralazine (1 mg/kg, i.p.) or an adrenalectomy barely affected mean arterial pressure in the CCI mice, whereas phentolamine (5 mg/kg, i.p.) lowered it. These results suggest that reduced blood flow in the skin contributes to neuropathic pain and that improving that blood flow with peripheral vasodilators, such as hydralazine, can alleviate it.
Learn More >Early childhood is a critical period for development, and early life stress may increase the risk of gastrointestinal diseases including irritable bowel syndrome (IBS). In rodents, neonatal maternal separation (NMS) induces bowel dysfunctions that resemble IBS. However, the underlying mechanisms remain unclear. Here we show that NMS induces expansion of intestinal stem cells (ISCs) and their differentiation toward secretory lineages including enterochromaffin (EC) and Paneth cells, leading to EC hyperplasia, increased serotonin production, and visceral hyperalgesia. This is reversed by inhibition of nerve growth factor (NGF)-mediated tropomyosin receptor kinase A (TrkA) signalling, and treatment with NGF recapitulates the intestinal phenotype of NMS mice in vivo and in mouse intestinal organoids in vitro. Mechanistically, NGF transactivates Wnt/β-catenin signalling. NGF and serotonin are positively correlated in the sera of diarrhea-predominant IBS patients. Together, our findings provide mechanistic insights into early life stress-induced intestinal changes that may translate into treatments for gastrointestinal diseases.
Learn More >Endometriosis concerns more than 10% of women of reproductive age, frequently leading to chronic pelvic pain. Repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) induces an analgesic effect. This effect on chronic pelvic pain is yet to be evaluated. The objective of this study was to assess the feasibility and effect of rTMS to reduce pain and improve quality of life (QoL) in patients with chronic pelvic pain due to endometriosis. This pilot, open-labelled prospective trial examined treatment by neuronavigated rTMS over M1, one session per day for 5 consecutive days. Each session consisted of 1.500 pulses at 10 Hz. We assessed tolerance, pain change and QoL until 4 weeks post treatment with a primary endpoint at day 8. Twelve women were included. No patients experienced serious adverse effects or a significant increase in pain. Nine women reported improvement on the Patient Global Impression of Change with a reduction in both pain intensity and pain interference (5.1 ± 1.4 vs. 4.1 ± 1.6, = 0.01 and 6.2 ± 2.1 vs. 4.2 ± 1.5, = 0.004, respectively). rTMS appears well tolerated and might be of interest for patients suffering from chronic pelvic pain for whom other treatments have failed. A randomized controlled trial is mandatory before proposing such treatment.
Learn More >Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for analgesia) and opioid-induced hyperalgesia (paradoxical increase in pain with opioid administration) can contribute to both poorly controlled pain and dose escalation. Hyperalgesia is particularly problematic as further opioid prescribing is largely futile. The mechanisms of opioid tolerance and hyperalgesia are complex, involving μ opioid receptor signalling pathways that offer opportunities for novel analgesic alternatives. The intracellular scaffold protein β-arrestin-2 is implicated in tolerance, hyperalgesia, and other opioid side-effects. Development of agonists biased against recruitment of β-arrestin-2 could provide analgesic efficacy with fewer side-effects. Alternative approaches include inhibition of peripheral μ opioid receptors and blockade of downstream signalling mechanisms, such as the non-receptor tyrosine kinase Src or N-methyl-D-aspartate receptors. Furthermore, it is prudent to use multimodal analgesic regimens to reduce reliance on opioids during the perioperative period. In the third paper in this Series we focus on clinical and mechanism-based understanding of tolerance and opioid-induced hyperalgesia, and discuss current and future strategies for pain management.
Learn More >Over the past decade there has been an increasing reliance on strong opioids to treat acute and chronic pain, which has been associated with a rising epidemic of prescription opioid misuse, abuse, and overdose-related deaths. Deaths from prescription opioids have more than quadrupled in the USA since 1999, and this pattern is now occurring globally. Inappropriate opioid prescribing after surgery, particularly after discharge, is a major cause of this problem. Chronic postsurgical pain, occurring in approximately 10% of patients who have surgery, typically begins as acute postoperative pain that is difficult to control, but soon transitions into a persistent pain condition with neuropathic features that are unresponsive to opioids. Research into how and why this transition occurs has led to a stronger appreciation of opioid-induced hyperalgesia, use of more effective and safer opioid-sparing analgesic regimens, and non-pharmacological interventions for pain management. This Series provides an overview of the epidemiology and societal effect, basic science, and current recommendations for managing persistent postsurgical pain. We discuss the advances in the prevention of this transitional pain state, with the aim to promote safer analgesic regimens to better manage patients with acute and chronic pain.
Learn More >Worldwide, the use of prescription opioid analgesics more than doubled between 2001 and 2013, with several countries, including the USA, Canada, and Australia, experiencing epidemics of opioid misuse and abuse over this period. In this context, excessive prescribing of opioids for pain treatment after surgery has been recognised as an important concern for public health and a potential contributor to patterns of opioid misuse and related harm. In the second paper in this Series we review the evolution of prescription opioid use for pain treatment after surgery in the USA, Canada, and other countries. We summarise evidence on the extent of opioid overprescribing after surgery and its potential association with subsequent opioid misuse, diversion, and the development of opioid use disorder. We discuss evidence on patient, physician, and system-level predictors of excessive prescribing after surgery, and summarise recent work on clinical and policy efforts to reduce such prescribing while ensuring adequate pain control.
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