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The endogenous metabolite methylglyoxal (MG) accumulates in diabetic patients with neuropathic pain. MG could be a mediator of diabetes-induced neuropathic pain via TRPA1 activation and sensitization of the voltage-gated sodium channel subtype 1.8. In this study, we tested the algogenic and sensitizing effect of MG in healthy human subjects using intracutaneous microinjections. The involvement of C-fibers was assessed via selective A-fiber nerve block, axon-reflex-erythema and via single nerve fiber recordings in humans (microneurography). Involvement of the transduction channels TRPA1 and TRPV1 in MG-induced pain sensation was investigated with specific ion channel blockers. We showed for the first time in healthy humans that MG induces pain, axon-reflex-erythema and long-lasting hyperalgesia via the activation of C-nociceptors. Predominantly the subclass of mechano-insensitive C-fibers is activated by MG. A-fibers contribute only negligibly to the burning pain sensation. Selective harmacological blockade of TRPA1 or TRPV1 showed that TRPA1 is crucially involved in MG-induced chemical pain sensation and heat hyperalgesia. In conclusion, the ctions of MG via TRPA1 activation on predominantly mechanoinsensitive C-fibers might be involved in spontaneously perceived pain in diabetic neuropathy and hyperalgesia as well as allodynia.
Pain has well established effects on attention. At present parallel literatures exist which have examined the effects of experimentally induced pain and consider cognitive performance in patients with chronic pain states. However, no study to date as attempted to examine the combined or differing effects of these two manifestations of pain in a single study. 24 participants with fibromyalgia (age 43.00, SD 28.28) and 26 healthy controls (age=36.07 SD=11.93) completed an n-back task, an attentional switching task, and a divided attention task, once during induced, moderately-intense pressure pain, and once without induced pain. Pain induction had selective effects on the n-back task, and an overall reduction in accuracy on the attentional switching task. Conversely, patients with fibromyalgia were selectively impaired in performance on the divided attention task. These data therefore suggest that the effects of pain are not summative and rather that the mechanisms that underlie the negative effects of pain on performance in acute and chronic states may differ. More research is needed to examine these mechanisms and how these negative effects can be ameliorated to treat cognitive symptoms in pain. Perspective: This article presents a study to examine the effects of an acute, induced pain model on cognitive performance in both fibromyalgia and healthy control populations. We established that the effects of acute and chronic pain on attention are different, suggesting different models need to be developed to understand these phenomena.
To compare adverse childhood experiences (ACEs) in women with chronic pelvic pain with a control group, and describe occurrence of specific ACEs in women with chronic pelvic pain.
Episodic migraine is a debilitating condition. Preventive therapy is used to reduce frequency, duration, or severity of attacks. This review discusses principles of preventive treatment with a focus on preventive treatment options for people with episodic migraine. Specifically discussed is evidence and use of new migraine-specific treatment options for episodic migraine, such as calcitonin gene-related peptide monoclonal antibodies, a noninvasive transcutaneous electrical nerve stimulation device, and a single-pulse transcranial magnetic stimulator device. Also discussed are evidence-based updates from the 2012 American Academy of Neurology and the American Headache Society guidelines regarding major medication classes recommended for preventive episodic migraine treatment.
There is growing interest in drug repositioning to find new therapeutic indications for drugs already approved for use in people. Lovastatin is an FDA approved drug that has been used clinically for over a decade as a lipid-lowering medication. While lovastatin is classically considered to act as a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor, the present series of studies reveal a novel lovastatin effect, that being as a Toll-like receptor 4 (TLR4) antagonist. Lovastatin selectively inhibits lipopolysaccharide (LPS)-induced TLR4-NF-κB activation without affecting signaling by other homologous TLRs. In vitro biophysical binding and cellular thermal shift assay (CETSA) show that lovastatin is recognized by TLR4's coreceptor myeloid differentiation protein 2 (MD-2). This finding is supported by molecular dynamics simulations that lovastatin targets the LPS binding pocket of MD-2 and lovastatin binding stabilizes the MD-2 conformation. In vitro studies of BV-2 microglial cells revealed that lovastatin inhibits multiple effects of LPS, including activation of NFkB; mRNA expression of tumor necrosis factor-a, interleukin-6 and cyclo-oxygenase 2; production of nitric oxide and reactive oxygen species; as well as phagocytic activity. Furthermore, intrathecal delivery of lovastatin over lumbosacral spinal cord of rats attenuated both neuropathic pain from sciatic nerve injury and expression of the microglial activation marker CD11 in lumbar spinal cord dorsal horn. Given the well-established role of microglia and proinflammatory signaling in neuropathic pain, these data are supportive that lovastatin, as a TLR4 antagonist, may be productively repurposed for treating chronic pain.
Clinicians have the dilemma of prescribing opioid or nonopioid analgesics to chronic pain patients; however, the impact of pain on our endogenous µ-opioid system and how our genetic profile (specifically catechol-O-methyltransferase [] polymorphisms) impacts its activation are currently unknown. Twelve chronic temporomandibular disorder (TMD) patients and 12 healthy controls (HCs) were scanned using positron emission tomography (PET) with [C]carfentanil, a selective radioligand for µ-opioid receptors (µORs). The first 45 min of each PET measured the µOR nondisplaceable binding potential (BP) at resting state, and the last 45 min consisted of a 20-min masseteric pain challenge with an injection of 5% hypertonic saline. Participants were also genotyped for different COMT alleles. There were no group differences in µOR BP at resting state (early phase). However, during the masseteric pain challenge (late phase), TMD patients exhibited significant reductions in µOR BP (decreased [C]carfentanil binding) in the contralateral parahippocampus ( = 0.002) compared to HCs. The µOR BP was also significantly lower in TMD patients with longer pain chronicity ( < 0.001). When considering genotype and chronic pain suffering, TMD patients with the Met substitution had higher pain sensitivity and longer pain chronicity with a 5-y threshold for µOR BP changes to occur in the parahippocampus. Together, the TMD diagnosis, Met substitution, and pain chronicity explained 52% of µOR BP variance in the parahippocampus (cumulative = 52%, < 0.003, and HC vs. TMD Cohen's effect size = 1.33 SD). There is strong evidence of dysregulation of our main analgesic and limbic systems in chronic TMD pain. The data also support precision medicine by helping identify TMD patients who may be more susceptible to chronic pain sensitivity and opioid dysfunction based on their genetic profile.
Chronic pain is a debilitating condition that often emerges as a clinical symptom of inflammatory diseases. It has therefore been widely accepted that the immune system critically contributes to the pathology of chronic pain. Microglia, a type of immune cell in the central nervous system, has attracted researchers' attention because in rodent models of neuropathic pain that develop strong mechanical and thermal hypersensitivity, histologically activated microglia are seen in the dorsal horn of spinal cord. Several kinds of cytokines are generated by damaged peripheral neurons and contribute to microglial activation at the distal site of the injury where damaged neurons send their projections. Microglia are known as key players in the surveillance of the local environment in the central nervous system and have a significant role of circuit remodeling by physical contact to synapses. Key molecules for the pathology of neuropathic pain exist in the activated microglia, but the factors driving pain-inducible microglial activation remain unclear. Therefore, to find the key molecules inducing activation of spinal microglia and to figure out the precise mechanism of how microglia modulate neuronal circuits in the spinal cord to form chronic pain state is a critical step for developing effective treatment of neuropathic pain.
Neuropeptide Y (NPY) modulates nociception in the spinal cord, but little is known about its mechanisms of release. We measured NPY release in situ using the internalization of its Y1 receptor in dorsal horn neurons. Y1 receptor immunoreactivity was normally localized to the cell surface, but addition of NPY to spinal cord slices increased the number of neurons with Y1 internalization in a biphasic fashion (ECs of 1 nM and 1 μM). Depolarization with KCl, capsaicin, or the protein kinase A activator 6-benzoyl-cAMP also induced Y1 receptor internalization, presumably by releasing NPY. NMDA receptor activation in the presence of BVT948, an inhibitor of protein tyrosine phosphatases, also released NPY. Electrical stimulation of the dorsal horn frequency-dependently induced NPY release; and this was decreased by the Y1 antagonist BIBO3304, the Nav channel blocker lidocaine, or the Cav2 channel blocker ω-conotoxin MVIIC. Dorsal root immersion in capsaicin, but not its electrical stimulation, also induced NPY release. This was blocked by CNQX, suggesting that part of the NPY released by capsaicin was from dorsal horn neurons receiving synapses from primary afferents and not from the afferent themselves. Mechanical stimulation in vivo, with rub or clamp of the hindpaw, elicited robust Y1 receptor internalization in rats with spared nerve injury but not sham surgery. In summary, NPY is released from dorsal horn interneurons or primary afferent terminals by electrical stimulation and by activation of TRPV1, PKA or NMDA receptors in. Furthermore, NPY release evoked by noxious and tactile stimuli increases after peripheral nerve injury.
Spinal cord stimulation (SCS) applied between T8 and T11 segments has been shown to be effective for the treatment of chronic pain of the lower back and limbs. However, the mechanism of the analgesic effect at these medullary levels remains unclear. Numerous studies relate glial cells with development and maintenance of chronic neuropathic pain. Glial cells are electrically excitable, which makes them a potential therapeutic target using SCS. The aim of this study is to report glia to neuron ratio in thoracic segments relevant to SCS, as well as to characterize the glia cell population at these levels. Dissections from gray and white matter of posterior spinal cord segments (T8, T9, intersection T9/T10, T10 and T11) were obtained from 11 human cadavers for histological analyses. Neuronal bodies and glial cells (microglia, astrocytes and oligodendrocytes) were immunostained, microphotographed and counted using image analysis software. Statistical analyses were carried out to establish significant differences of neuronal and glial populations among the selected segments, between the glial cells in a segment, and glial cells in white and gray matter. Results show that glia to neuron ratio in the posterior gray matter of the human spinal cord within the T8-T11 vertebral region is in the range 11 : 1 to 13 : 1, although not significantly different among vertebral segments. Glia cells are more abundant in gray matter than in white matter, whereas astrocytes and oligodendrocytes are more abundant than microglia (40 : 40 : 20). Interestingly, the population of oligodendrocytes in the T9/T10 intersection is significantly larger than in any other segment. In conclusion, glial cells are the predominant bodies in the posterior gray and white matter of the T8-T11 segments of the human spinal cord. Given the crucial role of glial cells in the development and maintenance of neuropathic pain, and their electrophysiological characteristics, anatomical determination of the ratio of different cell populations in spinal segments commonly exposed to SCS is fundamental to understand fully the biological effects observed with this therapy.
Opioids are widely prescribed for chronic pain, including neuropathic pain despite growing evidence of long-term harm. Previous preclinical studies have documented exacerbation of nociceptive hypersensitivity, including that induced by peripheral nerve injury, by morphine. The present series of behavioral studies sought to replicate and extend our prior research, which demonstrated a multi-month exacerbation of nociceptive hypersensitivity by a 5-day course of morphine initiated 10 days after nerve injury. The current studies demonstrate that enduring exacerbation of nociceptive hypersensitivity is not restricted to morphine, but rather is also created by the clinically relevant opioids fentanyl and oxycodone when these are likewise-administered for 5 days beginning 10 days after nerve injury. Furthermore, enduring exacerbation of nociceptive hypersensitivity is also observed when the same dosing regimen for either morphine, fentanyl, or oxycodone begins 1 month after nerve injury. Lastly, a striking result from these studies is that no such exacerbation of nociceptive hypersensitivity occurs when either morphine, fentanyl, or oxycodone dosing begins at the time of nerve injury. These results extend our previous findings that morphine exacerbates nociceptive hypersensitivity to the clinically relevant opioids fentanyl and oxycodone when administered after the development of nociceptive hypersensitivity, while also providing possible clinically-relevant insight into when these opioids can be safely administered and not exacerbate neuropathic pain.