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OBJECTIVEMotor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings.METHODSMale Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS.RESULTSMCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia.CONCLUSIONSThese results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.
Learn More >Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (HS) is involved in diabetes-induced hyperalgesia and allodynia. However, the molecular target through which HS induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in HS-induced hyperalgesia in diabetic rats.
Learn More >There is a substantial body of evidence indicating that corneal sensory innervation is affected by pathology in a range of diseases. However, there are no published studies that have directly assessed whether the nerve fiber density of the different subpopulations of corneal sensory neurons are differentially affected. The present study explored the possibility that the intraepithelial nerve fiber density of corneal polymodal nociceptors and cold thermoreceptors are differentially affected in mice fed with a high-fat high cholesterol (HFHC; 21% fat, 2% cholesterol) diet and in those that also have diabetes.
Learn More >Unexplained postoperative pain is one of the most feared complications of total knee arthroplasty (TKA). A persistent noxious peripheral stimulus, such as the pain of chronic knee osteoarthritis, can cause central sensitization in which the central nervous system becomes hyperexcitable, resulting in hypersensitivity to both noxious and non-noxious stimuli. Patients with central sensitization may be more susceptible to unexplained pain after TKA. Duloxetine, a selective serotonin norepinephrine reuptake inhibitor (SNRI), can ameliorate the pain associated with central sensitization, and we aimed to determine whether it could reduce postoperative pain and improve quality of recovery after TKA in patients with central sensitization.
Learn More >Sex has been speculated to be a predictor of the placebo and nocebo effect for many years, but whether this holds true or not has rarely been investigated. We utilized a placebo literature database on various aspects of the genuine placebo/nocebo response. In 2015, we had extracted 75 systematic reviews, meta-analyses, and meta-regressions performed in major medical areas (neurology, psychiatry, internal medicine). These meta-analyses were screened for whether sex/gender differences had been noted to contribute to the placebo/nocebo effect: in only 3 such analyses female sex was associated with a higher placebo effect, indicating poor evidence for a contribution of sex to it in RCTs. This was updated with another set of meta-analyses for the current review, but did not change the overall conclusion. The same holds true for 18 meta-analyses investigating adverse event (nocebo) reporting in RCT in the placebo arm of trials. We also screened our database for papers referring to sex/gender and the placebo effect in experimental studies, and identified 28 papers reporting 29 experiments. Their results can be summarized as follows: (a) Despite higher sensitivity of pain in females, placebo analgesia is easier to elicit in males; (b) It appears that conditioning is effective specifically eliciting nocebo effects; (c) Conditioning works specifically well to elicit placebo and nocebo effects in females and with nausea; (d) Verbal suggestions are not sufficient to induce analgesia in women, but work in men. These results will be discussed with respect to the question why nausea and pain may be prone to be responsive to sex/gender differences, while other symptoms are less. Lastly, we will discuss the apparent discrepancy between RCT with low relevance of sex, and higher relevance of sex in specific experimental settings. We argue that the placebo response is predominantly the result of a conditioning (learning) response in females, while in males it predominantly may be generated via (verbal) manipulating of expectancies. In RCT therefore, the net outcome of the intervention may be the same despite different mechanisms generating the placebo effect between the sexes, while in experimental work when both pathways are separated and explicitly explored, such differences may surface.
Learn More >Remifentanil is widely used in general anesthesia due to its reliability and rapid onset. However, remifentanil-induced postoperative hyperalgesia might be a challenge nowadays. Accumulating evidence suggests that the transient receptor potential vanilloid 1 (TRPV1) was involved in the development of neuropathic pain and hyperalgesia. However, the contribution of TRPV1 in modulating remifentanil-induced postoperative hyperalgesia is still unknown. The aim of this study is the contribution of TRPV1 to the surface expression of -methyl-d-aspartate (NMDA) receptors in remifentanil-induced postoperative hyperalgesia.
Learn More >Glutamate is a fundamental excitatory neurotransmitter in the mammalian central nervous system (CNS), playing key roles in memory, neuronal development, and synaptic plasticity. Moreover, excessive glutamate release has been implicated in neuronal cell death. There are both ionotropic and metabotropic glutamate receptors (mGluRs), the latter of which can be divided into eight subtypes and three subgroups based on homology sequence and their effects on cell signaling. Indeed, mGluRs exert fine control over glutamate activity by stimulating several cell-signaling pathways the activation of G protein-coupled (GPC) or G protein-independent cell signaling. The involvement of specific mGluRs in different forms of synaptic plasticity suggests that modulation of mGluRs may aid in the treatment of cognitive impairments related to several neurodevelopmental/psychiatric disorders and neurodegenerative diseases, which are associated with a high economic and social burden. Preclinical and clinical data have shown that, in the CNS, mGluRs are able to modulate presynaptic neurotransmission by fine-tuning neuronal firing and neurotransmitter release in a dynamic, activity-dependent manner. Current studies on drugs that target mGluRs have identified promising, innovative pharmacological tools for the treatment of neurodegenerative and neuropsychiatric conditions, including chronic pain.
Learn More >Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na/K ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy.
Learn More >With the approval of calcitonin gene-related peptide (CGRP) and CGRP receptor monoclonal antibodies by the Federal Drug Administration, a new era in the treatment of migraine patients is beginning. However, there are still many unknowns in terms of CGRP mechanisms of action that need to be elucidated to allow new advances in migraine therapies. CGRP has been studied both clinically and preclinically since its discovery. Here we review some of the preclinical data regarding CGRP in animal models of migraine.
Learn More >Pregabalin is commonly used as an analgesic for neuropathic pain. But pregabalin as an adjunct to a multimodal analgesic regimen – although standard clinical protocol in some settings – has remained controversial. This meta-analysis was conducted to identify the efficacy of pregabalin for management of postoperative pain in thoracotomy.
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