SP0034 Plasticity of pain modulation due to chronic pain

Chronic pain is a complex sensory, cognitive, and emotional experience that imposes a great personal, psychological, and socioeconomic burden on patients. An estimated 1.5 billion people worldwide are afflicted with chronic pain, which is often difficult to treat and may be resistant to the potent pain-relieving effects of opioid analgesics. Attention has therefore focused on advancing new pain therapies directed at the cannabinoid system because of its key role in pain modulation. Endocannabinoids and exogenous cannabinoids exert their actions primarily through Gi/o-protein coupled cannabinoid CB1 and CB2 receptors expressed throughout the nervous system. CB1 receptors are found at key nodes along the pain pathway and their activity gates both the sensory and affective components of pain. CB2 receptors are typically expressed at low levels on microglia, astrocytes, and peripheral immune cells. In chronic pain states, there is a marked increase in CB2 expression which modulates the activity of these central and peripheral immune cells with important consequences for the surrounding pain circuitry. Growing evidence indicate that interventions targeting CB1 or CB2 receptors improve pain outcomes in a variety of preclinical pain models. In this mini-review, we will highlight recent advances in understanding how cannabinoids modulate microglia function and its implications for cannabinoid-mediated analgesia, focusing on microglia-neuron interactions within the spinal nociceptive circuitry.

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The periaqueductal gray and descending pain modulation: why should we study them and what role do they play in chronic pain?

Journal of Neurophysiology ◽

10.1152/jn.00998.2014 ◽

2015 ◽

Vol 114 (4) ◽

pp. 2080-2083 ◽

Cited By ~ 17

Author(s):

Kasey S. Hemington ◽

Marie-Andrée Coulombe

Keyword(s):

Chronic Pain ◽

Back Pain ◽

Functional Connectivity ◽

Recent Literature ◽

Chronic Back Pain ◽

Periaqueductal Gray ◽

Pain Modulation ◽

Pain Research ◽

Descending Pain Modulation ◽

Pain Patients

In this Neuro Forum we discuss the significance of a recent study by Yu et al. ( Neuroimage Clin 6: 100–108, 2014). The authors examined functional connectivity of a key node of the descending pain modulation pathway, the periaqueductal gray (PAG), in chronic back pain patients. Altered PAG connectivity to pain-related regions was found; we place results within the context of recent literature and emphasize the importance of understanding the descending component of pain in pain research.

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Catastrophizing Interferes with Cognitive Modulation of Pain in Women with Fibromyalgia

Pain Medicine ◽

10.1093/pm/pny008 ◽

2018 ◽

Vol 19 (12) ◽

pp. 2408-2422 ◽

Cited By ~ 11

Author(s):

Laura D Ellingson ◽

Aaron J Stegner ◽

Isaac J Schwabacher ◽

Jacob B Lindheimer ◽

Dane B Cook

Keyword(s):

Central Nervous System ◽

Chronic Pain ◽

Nervous System ◽

Pain Catastrophizing ◽

Pain Modulation ◽

Critical Function ◽

Sensory Stimuli ◽

Brain Responses ◽

Increased Risk ◽

Pain Ratings

Abstract Background Pain modulation is a critical function of the nociceptive system that includes the ability to engage descending pain control systems to maintain a functional balance between facilitation and inhibition of incoming sensory stimuli. Dysfunctional pain modulation is associated with increased risk for chronic pain and is characteristic of fibromyalgia (FM). Catastrophizing is also common in FM. However, its influence on pain modulation is poorly understood. Objective To determine the role of catastrophizing on central nervous system processing during pain modulation in FM via examining brain responses and pain sensitivity during an attention-distraction paradigm. Methods Twenty FM patients and 18 healthy controls (CO) underwent functional magnetic resonance imaging while receiving pain stimuli, administered alone and during distracting cognitive tasks. Pain ratings were assessed after each stimulus. Catastrophizing was assessed with the Pain Catastrophizing Scale (PCS). Results The ability to modulate pain during distraction varied among FM patients and was associated with catastrophizing. This was demonstrated by significant positive relationships between PCS scores and pain ratings (P < 0.05) and brain responses in the dorsolateral prefrontal cortex (P < 0.01). Relationships between catastrophizing and pain modulation did not differ between FM and CO (P > 0.05). Conclusions FM patients with higher levels of catastrophizing were less able to distract themselves from pain, indicative of catastrophizing-related impairments in pain modulation. These results suggest that the tendency to catastrophize interacts with attention-resource allocation and may represent a mechanism of chronic pain exacerbation and/or maintenance. Reducing catastrophizing may improve FM symptoms via improving central nervous system regulation of pain.

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Spinal cord neural activity of patients with fibromyalgia and healthy controls during temporal summation of pain: an fMRI study

Journal of Neurophysiology ◽

10.1152/jn.00276.2021 ◽

2021 ◽

Vol 126 (3) ◽

pp. 946-956

Author(s):

Roland Staud ◽

Jeff Boissoneault ◽

Song Lai ◽

Marlin S. Mejia ◽

Riddhi Ramanlal ◽

...

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Neural Activity ◽

Central Sensitization ◽

Temporal Summation ◽

Time Course ◽

Pain Modulation ◽

Healthy Controls ◽

Fmri Study ◽

Second Pain

“Windup” and its behavioral correlate “temporal-summation-of-second pain” (TSSP) represent spinal cord mechanisms of pain augmentation associated with central sensitization and chronic pain. Fibromyalgia (FM) is a chronic pain disorder, where abnormal TSSP has been demonstrated. We used fMRI to study spinal cord and brainstem activation during TSSP. We characterized the time course of spinal cord and brainstem BOLD activity during TSSP which showed abnormal brainstem activity in patients with FM, possibly due to deficient pain modulation.

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Characterization of New TRPM8 Modulators in Pain Perception

International Journal of Molecular Sciences ◽

10.3390/ijms20225544 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5544 ◽

Cited By ~ 8

Author(s):

Carmen De Caro ◽

Claudia Cristiano ◽

Carmen Avagliano ◽

Alessia Bertamino ◽

Carmine Ostacolo ◽

...

Keyword(s):

Chronic Pain ◽

Pain Perception ◽

Transient Receptor Potential ◽

Pain Modulation ◽

The Body ◽

Sprague Dawley ◽

Transient Receptor Potential Melastatin ◽

Pain Models ◽

Excessive Activation

Background: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca2+-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. Experimental approach: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. Results: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. Conclusions: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain.

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Manganese-enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats

Molecular Brain ◽

10.1186/s13041-020-00687-1 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Myeounghoon Cha ◽

Songyeon Choi ◽

Kyeongmin Kim ◽

Bae Hwan Lee

Keyword(s):

Chronic Pain ◽

Nerve Injury ◽

Pain Perception ◽

Imaging Techniques ◽

Insular Cortex ◽

Pain Modulation ◽

Anterior Cingulate ◽

Related Area ◽

Mtor Inhibition ◽

The Brain

AbstractNeuropathic pain induced by a nerve injury can lead to chronic pain. Recent studies have reported hyperactive neural activities in the nociceptive-related area of the brain as a result of chronic pain. Although cerebral activities associated with hyperalgesia and allodynia in chronic pain models are difficult to represent with functional imaging techniques, advances in manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) could facilitate the visualization of the activation of pain-specific neural responses in the cerebral cortex. In order to investigate the alleviation of pain nociception by mammalian target of rapamycin (mTOR) modulation, we observed cerebrocortical excitability changes and compared regional Mn2+ enhancement after mTOR inhibition. At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1, and XL388) effects were compared within groups using MEMRI. Therein, signal intensities of the insular cortex (IC), primary somatosensory cortex of the hind limb region, motor cortex 1/2, and anterior cingulate cortex regions were significantly reduced after application of mTOR inhibitors (Torin1 and XL388). Furthermore, rostral-caudal analysis of the IC indicated that the rostral region of the IC was more strongly associated with pain perception than the caudal region. Our data suggest that MEMRI can depict pain-related signal changes in the brain and that mTOR inhibition is closely correlated with pain modulation in chronic pain rats.

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