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It is well recognized that in primates, including humans, noxious body stimulation evokes a neural response in the posterior bank of the central sulcus, in Brodmann cytoarchitectonic subdivisions 3b and 1 of the primary somatosensory cortex. This response is associated with the 1st/sharp pain and contributes to sensory discriminative aspects of pain perception and spatial localization of the noxious stimulus. However, neurophysiological studies in New World monkeys predict that in humans noxious stimulation also evokes a separate neural response-mediated by C-afferent drive and associated with the 2nd/burning pain-in the depth of the central sulcus in Brodmann area 3a (BA3a) at the transition between the somatosensory and motor cortices. To evoke such a response, it is necessary to use multi-second duration noxious stimulation, rather than brief laser pulses. Given the limited human pain-imaging literature on cortical responses induced by C-nociceptive input specifically within BA3a, here we used high spatial resolution 7T fMRI to study the response to thermonoxious skin stimulation. We observed the predicted response of BA3a in the depth of the central sulcus in five human volunteers. Review of the available evidence suggests that the nociresponsive region in the depth of the central sulcus is a structurally and functionally distinct cortical area that should not be confused with proprioceptive BA3a. It is most likely engaged in interoception and control of the autonomic nervous system, and contributes to the sympathetic response to noxious stimulation, arguably the most intolerable aspect of pain experience. Ablation of this region has been shown to reduce pain sensibility and might offer an effective means of ameliorating some pathological pain conditions.
Learn More >Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Ca3.2 T-type Ca channel activity by HS, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/HS/Ca3.2 pathways in the bladder pain development. Bladder pain (nociceptive behavior/referred hyperalgesia) and immuno-reactive CSE expression in the bladder were determined in CPA-treated female mice. Cell signaling was analyzed in urothelial T24 and macrophage-like RAW264.7 cells. The CPA-induced bladder pain was abolished by pharmacological inhibition of T-type Ca channels or CSE, and genetic deletion of Ca3.2. The CPA-induced CSE upregulation, as well as bladder pain was prevented by HMGB1 inactivation, inhibition of HMGB1 release from macrophages, antagonists of RAGE or P2X/P2X receptors, and N-acetylcysteine, an antioxidant. Acrolein, a metabolite of CPA, triggered ATP release from T24 cells. Adenosine triphosphate (ATP) stimulated cell migration via P2X/P2X, and caused HMGB1 release via P2X in RAW264.7 cells, which was dependent on p38MAPK/NF-κB signaling and reactive oxygen species (ROS) accumulation. Together, our data suggest that CPA, once metabolized to acrolein, causes urothelial ATP-mediated, redox-dependent HMGB1 release from macrophages, which in turn causes RAGE-mediated CSE upregulation and subsequent HS-targeted Ca3.2-dependent nociceptor excitation, resulting in bladder pain.
Learn More >Pain self-management is an effective, evidence-based treatment for chronic pain. Peer support, in which patients serve as coaches for other patients, has been effective in other chronic conditions and is a potentially promising approach to implementing pain self-management programs using fewer clinical resources.
Learn More >Satellite glial cells (SGCs) closely envelop cell bodies of neurons in sensory, sympathetic and parasympathetic ganglia. This unique organization is not found elsewhere in the nervous system. SGCs in sensory ganglia are activated by numerous types of nerve injury and inflammation. The activation includes upregulation of glial fibrillary acidic protein, stronger gap junction-mediated SGC-SGC and neuron-SGC coupling, increased sensitivity to ATP, downregulation of Kir4.1 potassium channels and increased cytokine synthesis and release. There is evidence that these changes in SGCs contribute to chronic pain by augmenting neuronal activity and that these changes are consistent in various rodent pain models and likely also in human pain. Therefore, understanding these changes and the resulting abnormal interactions of SGCs with sensory neurons could provide a mechanistic approach that might be exploited therapeutically in alleviation and prevention of pain. We describe how SGCs are altered in rodent models of four common types of pain: systemic inflammation (sickness behaviour), post-surgical pain, diabetic neuropathic pain and post-herpetic pain.
Learn More >The state of an animal prior to the application of a noxious stimulus can have a profound effect on their nociceptive threshold and subsequent behaviour. In mammals, the presence of acute stress preceding a painful event can have an analgesic effect whereas the presence of chronic stress can result in hyperalgesia. While considerable research has been conducted on the ability of stress to modulate mammalian responses to pain, relatively little is known about fish. This is of particular concern given that zebrafish () are an extensively used model organism subject to a wide array of invasive procedures where the level of stress prior to experimentation could pose a major confounding factor. This study, therefore, investigated the impact of both acute and chronic stress on the behaviour of zebrafish subjected to a potentially painful laboratory procedure, the fin clip. In stress-free individuals, those subjected to the fin clip spent more time in the bottom of the tank, had reduced swimming speeds and less complex swimming trajectories; however, these behavioural changes were absent in fin-clipped fish that were first subject to either chronic or acute stress, suggesting the possibility of stress-induced analgesia (SIA). To test this, the opioid antagonist naloxone was administered to fish prior to the application of both the stress and fin-clip procedure. After naloxone, acutely stressed fin-clipped zebrafish exhibited the same behaviours as stress-free fin-clipped fish. This indicates the presence of SIA and the importance of opioid signalling in this mechanism. As stress reduced nociceptive responses in zebrafish, this demonstrates the potential for an endogenous analgesic system akin to the mammalian system. Future studies should delineate the neurobiological basis of stress-induced analgesia in fish.
Learn More >To investigate whether chronic opioid therapy is associated with a higher risk of cancer among non-cancer patients with chronic pain.
Learn More >Studies in mouse, and to a lesser extent in rat, have revealed the neuroanatomical distribution of vesicular glutamate transporters (VGLUTs) and begun exposing the critical role of VGLUT2 and VGLUT3 in pain transmission. In the present study in rat we used specific riboprobes to characterize the transcript expression of all three VGLUTs in lumbar dorsal root ganglia (DRGs) and in the thoracolumbar, lumbar and sacral spinal cord. We show for the first time in rat a very discrete VGLUT3 expression in DRGs and in deep layers of the dorsal horn. We confirm the abundant expression of VGLUT2, both in DRGs and the spinal cord, including presumable motorneurons in the latter. As expected, VGLUT1 was present in many DRG neuron profiles, and in the spinal cord was mostly localized to neurons in the dorsal nucleus of Clarke. In rats with a 10-day long hindpaw inflammation, increased spinal expression of VGLUT2 transcript was detected by qRT-PCR, and intrathecal administration of the non-selective VGLUT inhibitor Chicago Sky Blue 6B resulted in reduced mechanical and thermal allodynia for up to 24 hours. In conclusion, our results provide a collective characterization of VGLUTs in rat DRGs and the spinal cord, demonstrate increased spinal expression of VGLUT2 during chronic peripheral inflammation, and support the use of spinal VGLUT blockade as a strategy for attenuating inflammatory pain.
Learn More >Objectives Static mechanical allodynia (SMA), i. e., pain caused by normally non-painful static pressure, is a prevalent manifestation of neuropathic pain (NP). Although SMA may significantly affect the patient's daily life, it is less well studied in the clinical context. We aimed to characterize SMA in women with chronic post-surgical NP (CPSNP) after breast cancer surgery. Our objective was to improve understanding of the clinical picture of this prevalent pain condition. This is a substudy of a previously published larger cohort of patients with intercostobrachial nerve injury after breast cancer surgery (Mustonen et al. Pain. 2019;160:246-56). Methods We studied SMA in 132 patients with CPSNP after breast cancer surgery. The presence, location, and intensity of SMA were assessed at clinical sensory examination. The patients gave self-reports of pain with the Brief Pain Inventory (BPI). We studied the association of SMA to type of surgery, oncological treatments, BMI, other pains, and psychological factors. General pain sensitivity was assessed by the cold pressor test. Results SMA was prevalent (84%) in this cohort whereas other forms of allodynia were scarce (6%). Moderate-to-severe SMA was frequently observed even in patients who reported mild pain in BPI. Breast and the side of chest were the most common locations of SMA. SMA was associated with breast surgery type, but not with psychological factors. Severe SMA, but not self-reported pain, was associated with lower cold pain tolerance. Conclusions SMA is prevalent in post-surgical NP after breast cancer surgery and it may represent a distinct NP phenotype. High intensities of SMA may signal the presence of central sensitization. Implications SMA should be considered when examining and treating patients with post-surgical NP after breast cancer surgery.
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