Loss of Temporal Inhibition of Nociceptive Information Is Associated With Aging and Bodily Pain

An age-related decline in endogenous pain inhibitory processes likely places older adults at an increased risk for chronic pain. Limited research indicates that older adults may be characterized by deficient offset analgesia, an inhibitory temporal sharpening mechanism that increases the detectability of minor decreases in noxious stimulus intensity. The primary purpose of the study was to examine age differences in offset analgesia in community-dwelling younger, middle-aged, and older adults. An additional aim of the study was to determine whether the magnitude of offset analgesia predicted self-reported bodily pain. Eighty-seven younger adults, 42 middle-aged adults, and 60 older adults completed 4 offset analgesia trials and 3 constant temperature trials in which a noxious heat stimulus was applied to the volar forearm for 40 seconds. The offset trials consisted of 3 continuous phases: an initial 10-second painful stimulus, either a 1.0°C or .4°C increase in temperature from the initial 10-second painful stimulus for 10 seconds, and either a 1.0°C or .4°C decrease back to the initial testing temperature for 20 seconds. During each trial, subjects rated pain intensity continuously using an electronic visual analog scale (0–100). All subjects also completed the Short-Form Health Survey-36 including the Bodily Pain subscale. The results indicated that older and middle-aged adults showed reduced offset analgesia compared with younger adults in the 1.0°C and .4°C offset trials. Furthermore, the magnitude of offset analgesia predicted self-reported bodily pain, with those exhibiting reduced offset analgesia reporting greater bodily pain. Dysfunction of this endogenous inhibitory system could increase the risk of developing chronic pain for middle-aged and older adults. Perspective Older and middle-aged adults showed reduced offset analgesia compared with younger adults. The significant association between reduced offset analgesia and pain in daily life supports the notion that pain modulatory deficits are associated with not just a chronic pain condition but with the experience of pain in general

Brain-heart pathways to blood pressure-related hypoalgesia

OBJECTIVE: High blood pressure (BP) is associated with reduced pain sensitivity, known as BP-related hypoalgesia. The underlying neural mechanisms remain uncertain, yet arterial baroreceptor signaling, occurring at cardiac systole, is implicated. We examined normotensives using functional neuroimaging (fMRI) and pain stimulation during distinct phases of the cardiac cycle to test the hypothesized neural mediation of baroreceptor-induced attenuation of pain. METHODS: Eighteen participants (10 women; 32.7 ± 6.5 years) underwent BP monitoring over one week at home, and individual pain thresholds were determined in the lab. Subsequently, participants were administered unpredictable painful and non-painful electrocutaneous shocks (stimulus type), timed to occur either at systole or diastole (cardiac phase) in an event-related design. After each trial, participants evaluated their subjective experience. RESULTS: Subjective pain was lower for painful stimuli administered at systole compared to diastole, F1, 2283 = 4.82; p = 0.03. Individuals with higher baseline BP demonstrated overall lower pain perception, F1, 2164 = 10.47; p < 0.0001. Within the brain, painful stimulation activated somatosensory areas, prefrontal cortex, cingulate cortex, posterior insula, amygdala, and the thalamus. Stimuli delivered during systole (concurrent with baroreceptor discharge) activated areas associated with heightened parasympathetic drive. No stimulus type x cardiac phase interaction emerged except for a small cluster located in the right parietal cortex. CONCLUSIONS: We confirm the negative associations between BP and pain, highlighting the antinociceptive impact of baroreceptor discharge. Neural substrates associated with baroreceptor/BP-related hypoalgesia include superior parietal lobule, precentral and lingual gyrus, regions typically involved in the cognitive aspects of pain experience

From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain Relief in the Clinic

The use of electricity for analgesic effects has a long history and yet currently neuromodulation devices based on electrical stimulation are typically restricted to being a last resort intervention for pain patients after the failure of pharmacological treatments. Whilst spinal cord stimulation is an established intervention for intractable neuropathic pain, the use of neuromodulation for other forms of pain and targeting different aspects of pain processing is less well established. Non-invasive neuromodulation as part of a standard intervention for pain relief would be ideal for without long term treatment of a chronic pain condition as it would avoid the inevitable side effects associated with long-term use of pharmacological interventions or interactions between different drug treatments. This is particularly relevant as chronic pain can be associated with diseases that would require pharmacological treatment for the primary condition. However, there is currently both a deficit in understanding the mechanisms of the different non-invasive devices and also in how these devices may facilitate pain relief for specific conditions. This review will focus on the application of electric currents non-invasively to different sites for pain relief and outline the future potential of these technologies

Exercise therapy for knee osteoarthritis pain:how does it work? A study protocol for a randomised controlled trial

INTRODUCTION: Muscle strengthening training (MST) and behavioural graded activity (BGA) show comparable effects on knee osteoarthritic (KOA) pain, but the mechanisms of action remain unclear. Both exercise-induced anti-inflammation and central sensitisation are promising pathways for pain relief in response to exercise therapy in patients with KOA: MST has the potential to decrease inflammation and BGA has the potential to decrease central sensitisation. Hence, this study aims to examine inflammation and central sensitisation as mediators for the effect of MST and/or BGA on pain in patients with KOA. METHODS AND ANALYSIS: The Knee OsteoArthritis PAIN trial started on 10 January 2020 (anticipated end: April 2024). The three-arm clinical trial aims to recruit 90 KOA patients who will be randomly allocated to 12 weeks of (1) MST, (2) BGA or (3) care as usual. Assessments will be performed at baseline, 13 and 52 weeks after finishing the intervention. Outcomes, including pain (Knee injury and Osteoarthritis Outcome Score), were chosen in line with the OARSI recommendations for clinical trials of rehabilitation interventions for OA and the IMMPACT/OMERACT recommendations for the assessment of physical function in chronic pain clinical trials. Inflammation as well as features of central sensitisation (including conditioned pain modulation, offset analgesia, temporal summation of pain and event-related potentials following electrical stimulation), will be considered as treatment mediators. A multiple mediators model will be estimated with a path-analysis using structural equation models. In July 2023, all 90 KOA patients have been included and 42 participants already finished the study. ETHICS AND DISSEMINATION: This study obtained ethics approval (B.U.N. 143201941843). Unravelling the mechanisms of action of exercise therapy in KOA will not only be extremely valuable for researchers, but also for exercise immunology and pain scientists and clinicians. TRIAL REGISTRATION NUMBER: NCT04362618.</p

Exercise therapy for knee osteoarthritis pain:how does it work? A study protocol for a randomised controlled trial

INTRODUCTION: Muscle strengthening training (MST) and behavioural graded activity (BGA) show comparable effects on knee osteoarthritic (KOA) pain, but the mechanisms of action remain unclear. Both exercise-induced anti-inflammation and central sensitisation are promising pathways for pain relief in response to exercise therapy in patients with KOA: MST has the potential to decrease inflammation and BGA has the potential to decrease central sensitisation. Hence, this study aims to examine inflammation and central sensitisation as mediators for the effect of MST and/or BGA on pain in patients with KOA. METHODS AND ANALYSIS: The Knee OsteoArthritis PAIN trial started on 10 January 2020 (anticipated end: April 2024). The three-arm clinical trial aims to recruit 90 KOA patients who will be randomly allocated to 12 weeks of (1) MST, (2) BGA or (3) care as usual. Assessments will be performed at baseline, 13 and 52 weeks after finishing the intervention. Outcomes, including pain (Knee injury and Osteoarthritis Outcome Score), were chosen in line with the OARSI recommendations for clinical trials of rehabilitation interventions for OA and the IMMPACT/OMERACT recommendations for the assessment of physical function in chronic pain clinical trials. Inflammation as well as features of central sensitisation (including conditioned pain modulation, offset analgesia, temporal summation of pain and event-related potentials following electrical stimulation), will be considered as treatment mediators. A multiple mediators model will be estimated with a path-analysis using structural equation models. In July 2023, all 90 KOA patients have been included and 42 participants already finished the study. ETHICS AND DISSEMINATION: This study obtained ethics approval (B.U.N. 143201941843). Unravelling the mechanisms of action of exercise therapy in KOA will not only be extremely valuable for researchers, but also for exercise immunology and pain scientists and clinicians. TRIAL REGISTRATION NUMBER: NCT04362618.</p

Identification of neural networks that contribute to motion sickness through principal components analysis of fos labeling induced by galvanic vestibular stimulation

Motion sickness is a complex condition that includes both overt signs (e.g., vomiting) and more covert symptoms (e.g., anxiety and foreboding). The neural pathways that mediate these signs and symptoms are yet to identified. This study mapped the distribution of c-fos protein (Fos)-like immunoreactivity elicited during a galvanic vestibular stimulation paradigm that is known to induce motion sickness in felines. A principal components analysis was used to identify networks of neurons activated during this stimulus paradigm from functional correlations between Fos labeling in different nuclei. This analysis identified five principal components (neural networks) that accounted for greater than 95% of the variance in Fos labeling. Two of the components were correlated with the severity of motion sickness symptoms, and likely participated in generating the overt signs of the condition. One of these networks included neurons in locus coeruleus, medial, inferior and lateral vestibular nuclei, lateral nucleus tractus solitarius, medial parabrachial nucleus and periaqueductal gray. The second included neurons in the superior vestibular nucleus, precerebellar nuclei, periaqueductal gray, and parabrachial nuclei, with weaker associations of raphe nuclei. Three additional components (networks) were also identified that were not correlated with the severity of motion sickness symptoms. These networks likely mediated the covert aspects of motion sickness, such as affective components. The identification of five statistically independent component networks associated with the development of motion sickness provides an opportunity to consider, in network activation dimensions, the complex progression of signs and symptoms that are precipitated in provocative environments. Similar methodology can be used to parse the neural networks that mediate other complex responses to environmental stimuli. © 2014 Balaban et al

Central mechanisms of offset analgesia

Reduction from a more to a less noxious stimulus intensity produces a disproportionate but transient decrease in perceived pain. Although the relationship between the central nervous system and this offset analgesia has come under investigation using brain imaging, whether offset analgesia is primarily mediated by central rather than peripheral mechanisms has not been established. Here we investigate this question in healthy volunteers using thermal stimuli while recording continuous pain ratings. We constructed a composite stimulus using one Peltier thermode to deliver a constant painful test stimulus while a separate thermode coincidentally delivered a shorter but more intense conditioning stimulus at a distinct location. Three spatial configurations were investigated all delivering stimulation to the ventral forearm either proximally or distally from one another on the same forearm or with thermodes on opposing forearms. We demonstrate a decrease in test stimulus pain levels following offset of an ipsilateral but not contralateral conditioning stimulus. This decrease is comparable in magnitude to that observed during a single thermode classic offset analgesia stimulation. The manifestation of analgesia in one sensory field following cessation of stimulation in a distinct sensory field shows antinociceptive adaptation of primary afferent neurons is unnecessary to produce offset analgesia, and demonstrates central mechanisms are sufficient to achieve temporal filtering of nociceptive information during stimulus offset.2017-08-0

The Effects of Cannabidiol and Analgesic Expectancies on Experimental Pain Reactivity in Healthy Adults: A Balanced Placebo Design Trial

Experimental pain trials have been unable to determine whether cannabinoid analgesia is attributable to intoxication, analgesic expectancies, and/or pharmacological action. One approach to resolving this issue involves testing the effects of analgesic expectancies and cannabidiol (CBD), a non-psychoactive cannabinoid, on human pain reactivity using a balanced placebo design. Despite its frequent use for pain relief, no experimental research has tested the analgesic effects of CBD in humans. Using a within-subjects 2 x 2 balanced placebo factorial design, we experimentally tested the effects of CBD and expectancies for receiving CBD on pain reactivity (i.e., pain threshold, tolerance, intensity, unpleasantness, conditioned pain modulation, offset analgesia) by manipulating both drug administration (given inactive substance or given CBD) and instructions (told inactive substance or told CBD) among 15 healthy humans. Participants completed 4 separate experimental sessions over the course of 4 weeks and were assigned to a different manipulation condition at each session: told inactive – given inactive (control); told active – given active (expectancy+drug); told inactive – given active (drug); and told active – given inactive (expectancy). We did not find significant effects for pain threshold, tolerance, or intensity. We found significant reductions in pain unpleasantness for the expectancy, drug, and expectancy+drug conditions when compared to the control condition. We also observed significant increases in CPM (e.g., greater pain inhibition) in the expectancy and drug conditions. Lastly, we found a significant main effect of instructions on OA, such that the OA response was significantly larger (e.g., greater pain inhibition) when participants were told that they received CBD, regardless of drug content. Overall, our results indicated that separate pain outcomes can be differentially affected by CBD and/or expectancies for receiving CBD. These findings suggest that the analgesic profile for CBD is complex and multifaceted