The limited success in translating basic science findings into effective pain management therapies reflects, in part, the difficulty in reliably assessing pain in experimental animals. This shortcoming is particularly acute in the field of chronic, ongoing pain. Quantitative analysis of facial expressions—the grimace score—was introduced as a promising tool, however, it is thought to reliably assess only pain of short or medium duration (minutes to hours). Here, we test the hypothesis that grimace scores are a reliable metric of ongoing neuropathic pain, by testing the prediction that chronic constriction injury of the infraorbital nerve (CCI-ION) will evoke significant increases in grimace scale scores. Mice and rats were subjected to CCI-ION, and tested for changes in mechanical hypersensitivity and in grimace scores, 10 or more days after surgery. Both rats and mice with CCIION had significantly higher grimace scores, and significantly lower thresholds for withdrawal from mechanical stimuli applied to the face, compared to sham-operated animals. Fentanyl reversed the changes in rat grimace scale scores, suggesting that these scores reflect pain perception. These findings validate the grimace scale as a reliable and sensitive metric for the assessment of ongoing pain in a rodent model of chronic, trigeminal neuropathic pain.
The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We hypothesized that PB hyperactivity influences chronic pain behavior after trigeminal nerve injury in rats. Following induction of neuropathic pain using the chronic constriction injury of the infraorbital nerve (CCI-ION) model, rats displayed spontaneous markers of pain and mechanical hyperalgesia extending beyond the receptive field of the injured nerve. PB neurons recorded from rats with CCI-ION displayed amplified activity, manifesting as significantly longer responses to sensory stimuli, compared to shams. These findings suggest that chronic neuropathic pain involves PB hyperactivity.
Traumatic brain injury (TBI) causes microglial activation and related neurotoxicity that contributes to chronic neurodegeneration and loss of neurological function. Selective activation of metabotropic glutamate receptor 5 (mGluR5) by the orthosteric agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), is neuroprotective in experimental models of TBI, and has potent anti-inflammatory effects in vitro. However, the therapeutic potential of CHPG is limited due to its relatively weak potency and brain permeability. Highly potent, selective and brain penetrant mGluR5 positive allosteric modulators (PAMs) have been developed and show promise as therapeutic agents. We evaluated the therapeutic potential of a novel mGluR5 PAM, VU0360172, after controlled cortical impact (CCI) in mice. Vehicle, VU0360172, or VU0360172 plus mGluR5 antagonist (MTEP), were administered systemically to CCI mice at 3 h post-injury; lesion volume, hippocampal neurodegeneration, microglial activation, and functional recovery were assessed through 28 days post-injury. Anti-inflammatory effects of VU0360172 were also examined in vitro using BV2 and primary microglia. VU0360172 treatment significantly reduced the lesion, attenuated hippocampal neurodegeneration, and improved motor function recovery after CCI. Effects were mediated by mGluR5 as co-administration of MTEP blocked the protective effects of VU0360172. VU0360172 significantly reduced CD68 and NOX2 expression in activated microglia in the cortex at 28 days post-injury, and also suppressed proinflammatory signaling pathways in BV2 and primary microglia. In addition, VU0360172 treatment shifted the balance between M1/M2 microglial activation states towards an M2 pro-repair phenotype. This study demonstrates that VU0360172 confers neuroprotection after experimental TBI, and suggests that mGluR5 PAMs may be promising therapeutic agents for head injury.
Introduction: Many clinical trials fail because of placebo responses. Prior therapeutic experiences and patients' expectations may affect the capacity to respond to placebos in chronic disorders. Objective: The scope of this study in 763 chronic orofacial pain and healthy study participants was to compare the magnitude and prevalence of placebo effects and determine the putative role of prior therapeutic experiences vs. expectations. Methods: We tested placebo propensity in a laboratory setting by using 2 distinct levels of individually tailored painful stimulations (high pain and low pain) to reinforce expectations and provide a hypoalgesic experience (conditioning phase). Afterwards, both levels of pain were surreptitiously set at a moderate pain level to test for placebo effects (testing phase). Pain and expectation ratings were assessed as primary outcomes using visual analog scales. Results: In both chronic pain and healthy participants, placebo effects were similar in magnitude, with the larger prevalence of responders in the healthy participants. Although chronic pain participants reported higher pain relief expectations, expectations did not account for the occurrence of placebo effects. Rather, prior experience via conditioning strength mediated placebo effects in both pain and healthy participants. Conclusions: These findings indicate that participants with chronic pain conditions display robust placebo effects that are not mediated by expectations but are instead directly linked to prior therapeutic experiences. This confirms the importance of assessing the therapeutic history while raising questions about the utility of expectation ratings. Future research is needed to enhance prediction of responses to placebos, which will ultimately improve clinical trial designs.
Immersive virtual reality (VR) consists of immersion in artificial environments through the use of real-time render technologies and the latest generation devices. The users feel just as immersed as they would feel in an everyday life situation, and this sense of presence seems to have therapeutic potentials. However, the VR mechanisms remain only partially known. This study is novel in that, for the first time in VR research, appropriate controls for VR contexts, immersive characteristics (ie, control VR), and multifaceted objective and subjective outcomes were included in a within-subject study design conducted on healthy participants. Participants received heat thermal stimulations to determine how VR can increase individual heat-pain tolerance limits (primary outcome) measured in degrees Celsius and seconds while recording concurrent autonomic responses. We also assessed changes in pain unpleasantness, mood, situational anxiety, and level of enjoyment (secondary outcomes). The VR induced a net gain in heat-pain tolerance limits that was paralleled by an increase of the parasympathetic responses. VR improved mood, situational anxiety, and pain unpleasantness when participants perceived the context as enjoyable, but these changes did not influence the increases in pain tolerance limits. Distraction increased pain tolerance limits but did not induce such mood and physiological changes. Immersive VR has been anecdotally applied to improve acute symptoms in contexts such as battlefield, emergency, and operating rooms. This study provides a mechanistic framework for VR as a low-risk, nonpharmacological intervention, which regulates autonomic, affective (mood and situational anxiety), and evaluative (subjective pain and enjoyment ratings) responses associated with acute pain.
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