Browse by Audience
Memantine (MEM) is one of the important clinical medications in treating moderate to severe Alzheimer disease. The effect of MEM on preventing or treating punctate allodynia has been thoroughly studied but not on the induction of dynamic allodynia. The aim of this study is to investigate whether MEM could prevent the induction of dynamic allodynia and its underlying spinal mechanisms. 1)in vivo SNI pain model, pretreatment with MEM at a lower dose (10nmol, i.t.; MEM-10) selectively prevented the induction of dynamic allodynia, but not the punctate allodynia. 2) Pretreatment with either MK801-10 (MK801-10nmol, i.t.) or higher dose of MEM (30nmol, i.t.; MEM-30) prevented the induction of both dynamic and punctate allodynia. 3) MEM-10 showed significant effect on the inhibition of the SNI induced overactivation of microglia in spinal dorsal horn. 4) In contrast, in CFA model, MEM-10 neither affected the CFA injection induced activation of microglia in spinal dorsal horn nor the induction of dynamic allodynia. 5) Immunohistology studies showed Kir2.1 channel distributed widely and co-localized with microglia in the spinal dorsal horn of mice. 6) Pretreatment with either minocycline, a microglia inhibitor, or ML133, a Kir2.1 inhibitor, both selectively prevented the overactivation of microglia in spinal dorsal horn, and the induction of dynamic allodynia following SNI. The selectively inhibitory effect on the induction of dynamic allodynia in SNI model by low dose of the memantine (MEM-10) was tightly correlated with the blockade of microglia Kir2.1 channel to suppress the microglia activation.
Learn More >Fibromyalgia syndrome (FM) is an enigma. During the past three decades, with the gradual acceptance of the validity of FM, it is variously under-, over and misdiagnosed. Evidence-based interdisciplinary guidelines have suggested a comprehensive clinical assessment to avoid this diagnostic conundrum. Every patient with chronic pain should be screened for chronic widespread pain (pain in four of five body regions) (CWP). Those with CWP should be screened for presence of additional major symptoms of FM: unrefreshed sleep and fatigue. A complete medical (including drug) history and complete physical examination is mandatory in the evaluation of a patient with CWP in order to consolidate the diagnosis of FM or identify features that may point to some other condition that may have a presentation similar to FM. Limited simple laboratory testing is recommended to screen for possible other diseases. The 2016 criteria may be used to further confirm the clinical diagnosis of FM. In consideration of the differential diagnosis of FM, attention should be paid to the presence of other chronic overlapping pain conditions and of mental disorders. FM as a stand alone diagnosis is however rare, as most patients with FM meet criteria for other chronic overlapping pain conditions or mental disorders. The severity of FM should be assessed in order to direct treatment approaches and help inform the likely outcome for an individual patient.
Learn More >Childhood trauma has been linked to neuropathic pain in noncancer populations, but its relationship with cancer treatment-related neuropathic pain is unknown.
Learn More >Cyclic nucleotide signaling in sensory neuron hyperexcitability and chronic pain after nerve injury.
The cyclic nucleotide signaling, including cAMP-PKA and cGMP-PKG pathways, has been well known to play critical roles in regulating cellular growth, metabolism and many other intracellular processes. In recent years, more and more studies have uncovered the roles of cAMP and cGMP in the nervous system. The cAMP and cGMP signaling mediates chronic pain induced by different forms of injury and stress. Here we summarize the roles of cAMP-PKA and cGMP-PKG signaling pathways in the pathogenesis of chronic pain after nerve injury. In addition, acute dissociation and chronic compression of the dorsal root ganglion (DRG) neurons, respectively, leads to neural hyperexcitability possibly through PAR2 activation-dependent activation of cAMP-PKA pathway. Clinically, radiotherapy can effectively alleviate bone cancer pain at least partly through inhibiting the cancer cell-induced activation of cAMP-PKA pathway. Roles of cyclic nucleotide signaling in neuropathic and inflammatory pain are also seen in many other animal models and are involved in many pro-nociceptive mechanisms including the activation of hyperpolarization-activated cyclic nucleotide (HCN)-modulated ion channels and the exchange proteins directly activated by cAMP (EPAC). Further understanding the roles of cAMP and cGMP signaling in the pathogenesis of chronic pain is theoretically significant and clinically valuable for treatment of chronic pain.
Learn More >Stress facilitates pain perception and sensitizes pain pathways，but the underlying mechanism is still unclear. The purpose of this study was to investigate whether activation of 5-hydroxytryptamine (5-HT) subtype-3 receptor in the spinal cord contributes to somatic hyperalgesia induced by repeated 3 day forced swim (FS) in the estradiol (E2) replacement rats after ovariectomy (OVx). Somatic sensitivity was assessed by thermal withdrawal latency to radiant heat and mechanical withdrawal threshold to von Frey filaments. The expression of 5-HT3A receptor in the L4-L5 dorsal spinal cord was examined by Western blot. Repeated FS stress reduced the thermal withdrawal latency and mechanical withdrawal threshold, and the presence of E2 exaggerated this hyperalgesia. The expression of 5-HT3A receptor in the L4-L5 dorsal spinal cord increased significantly following repeated FS in E2 replacement rats. Intrathecal injection of 5-HT3 receptor antagonist Y-25130 blocked the somatic hyperalgesia induced by FS stress. These data indicate that 5-HT3 receptor activation through the descending facilitation system contributes to the somatic hyperalgesia evoked by FS stress. The results may provide a new therapeutic avenue for alleviating pain induced by stress.
Learn More >Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors and channels. The dysregulation of trafficking of voltage-gated ion channels is an emerging mechanism in the etiology of neuropathic pain. We identify increased phosphorylation of collapsin response mediator protein 2 (CRMP2), a protein reported to regulate presynaptic voltage-gated calcium and sodium channels. A spared nerve injury (SNI) increased expression of a cyclin dependent kinase 5 (Cdk5)-phosphorylated form of CRMP2 in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) in the ipsilateral (injured) versus the contralateral (non-injured) sites. Biochemical fractionation of spinal cord from SNI rats revealed the increase in Cdk5-mediated CRMP2 phosphorylation to be enriched to pre-synaptic sites. CRMP2 has emerged as a central node in assembling nociceptive signaling complexes. Knockdown of CRMP2 using a small interfering RNA (siRNA) reversed SNI-induced mechanical allodynia implicating CRMP2 expression as necessary for neuropathic pain. Intrathecal expression of a CRMP2 resistant to phosphorylation by Cdk5 normalized SNI-induced mechanical allodynia, whereas mimicking constitutive phosphorylation of CRMP2 resulted in induction of mechanical allodynia in naïve rats. Collectively, these results demonstrate that Cdk5-mediated CRMP2 phosphorylation is both necessary and sufficient for peripheral neuropathic pain.
Learn More >Effective pharmacological treatment options for chronic pain remain very limited, and continued reliance on opioid analgesics has contributed to an epidemic in the U.S. On the other hand, non-pharmacologic neuromodulatory interventions provide a promising avenue for relief of chronic pain without the complications of dependence and addiction. An especially attractive neuromodulation strategy is to optimize endogenous pain regulatory circuits. The prefrontal cortex (PFC) is known to provide top-down control of pain, and hence neuromodulation methods that selectively enhance the activities in this brain region during pain episodes have the potential to provide analgesia. In this study, we designed a low-frequency (2 Hz) electrical stimulation protocol to provide temporally and spatially specific enhancement of the prefrontal control of pain in rats. We showed that low-frequency electrical stimulation of the prelimbic region of the PFC relieved both sensory and affective responses to acute pain in naïve rats. Furthermore, we found that low-frequency electrical stimulation of the PFC also attenuated mechanical allodynia in a rat model of chronic pain. Together, our findings demonstrated that low-frequency electrical stimulation of the PFC represents a promising new method of neuromodulation to inhibit pain.
Learn More >Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system. Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic). Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation. One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia . Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells. The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release. This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R's role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception. We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoidmediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons. This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.
Learn More >Disability and movement-related pain are major symptoms of joint disease, motivating the development of methods to quantify motor behaviour in rodent joint pain models. We compared effects on behaviour, assessed the levels of biochemical mediators and made a detailed histopathological evaluation after induction of rat monoiodoacetate (MIA) monoarthritis into the ankle or knee joint.
Learn More >