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The prime task of nociceptors is the transformation of noxious stimuli into action potentials that are propagated along the neurites of nociceptive neurons from the periphery to the spinal cord. This function of nociceptors relies on the coordinated operation of a variety of ion channels. In this review, we summarize how members of nine different families of ion channels expressed in sensory neurons contribute to nociception. Furthermore, data on 35 different types of G protein coupled receptors are presented, activation of which controls the gating of the aforementioned ion channels. These receptors are not only targeted by more than 20 separate endogenous modulators, but can also be affected by pharmacotherapeutic agents. Thereby, this review provides information on how ion channel modulation via G protein coupled receptors in nociceptors can be exploited to provide improved analgesic therapy.
Learn More >OBJECTIVETrigeminal neuralgia (TN) is facial pain that is usually caused by neurovascular compression syndrome and is characterized by suddenly intense and paroxysmal pain. Radiofrequency lesioning (RFL) is one of the major treatments for TN, but the treatment response for RFL is sometimes inconsistent, and the recurrence of TN is not uncommon. This study aimed to estimate the outcome predictors of TN treated with RFL by using the parameters of diffusion tensor imaging (DTI).METHODSFifty-one patients with TN who were treated with RFL were enrolled in the study. MRI was performed in all patients within 1 week before surgery. The visual analog scale was used to evaluate symptom severity at three time points: before, 1 week after, and 3 months after RFL. The involved cisternal segment of the trigeminal nerves was manually selected, and the histograms of each of the diffusivity metrics-including the apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD)-were measured. The differences in the means, as well as the kurtosis and skewness of each of the diffusivity metrics between the nonrecurrent and recurrent groups, were then analyzed using the Mann-Whitney U-test.RESULTSThere were significantly lower kurtosis values (a broader peak of the distributional curves) for both FA and ADC in the recurrent group (p = 0.0004 and 0.015, respectively), compared to the nonrecurrent group. The kurtoses of AD and RD, as well as the mean and skewness of all other diffusivity metrics, did not show significant differences between the two groups.CONCLUSIONSThe pretreatment diffusivity metrics of DTI and ADC may be feasible imaging biomarkers for predicting the outcome of TN after RFL. A clarification of the kurtosis value of FA and ADC is helpful for determining the prognosis of patients after RFL.
Learn More >Neuropathic pain can develop after nerve injury, leading to a chronic condition with spontaneous pain and hyperalgesia. Pain is typically restricted to the side of the injured nerve, but may occasionally spread to the contralateral side, a condition that is often referred to as mirror-image pain. Mechanisms leading to mirror-image pain are not completely understood, but cannabinoid CB2 receptors have been implicated. In this study, we use genetic mouse models to address the question if CB2 receptors on neurons or on microglia/macrophages are involved. First, we show that a GFP reporter protein under control of the CB2 promoter is induced upon partial sciatic nerve ligation in spinal cord, dorsal root ganglia, and highest in sciatic nerve macrophages, but not in neurons. Mice which lack CB2 receptors specifically on myeloid cells (microglia, macrophages) developed a mirror-image allodynia [treatment F = 45.69, p < 0.0001] similar to constitutive CB2 receptor knockout mice [treatment F = 92.41, p < 0.0001]. Such a phenotype was not observed after the deletion of CB2 from neurons [treatment F = 0.1315, p = 0.7180]. This behavioral pain phenotype was accompanied by an increased staining of microglia in the dorsal horn of the spinal cord, as evidenced by an enhanced Iba 1 expression [CB2KO, p = 0.0175; CB2-LysM, p = 0.0425]. Similarly, myeloid-selective knockouts showed an increased expression of the leptin receptor in the injured ipsilateral sciatic nerve, thus further supporting the notion that leptin signaling contributes to the increased neuropathic pain responses of CB2 receptor knockout mice. We conclude that CB2 receptors on microglia and macrophages, but not on neurons, modulate neuropathic pain responses.
Learn More >The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs are currently being developed, among which the small molecule CGRP receptor antagonists, gepants, and the 5-HT receptor agonist lasmiditan. Whether treatment with these drugs carries the same risk for developing MOH is currently unknown.
Learn More >Highly effective and safe drugs for the treatment of neuropathic pain are urgently required and it was shown that blocking T-type calcium channels can be a promising strategy for drug development for neuropathic pain. We have developed pyrrolidine-based T-type calcium channel inhibitors by structural hybridization and subsequent assessment of in vitro activities against Ca3.1 and Ca3.2 channels. Profiling of in vitro ADME properties of compounds was also carried out. The representative compound 17h showed comparable in vivo efficacy to gabapentin in the SNL model, which indicates T-type calcium channel inhibitors can be developed as effective therapeutics for neuropathic pain.
Learn More >The 5-HT receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, K = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain C = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.
Learn More >The nociceptive withdrawal reflex (NWR) is a polysynaptic spinal reflex protecting the body from harmful stimuli. Two different methods to assess its' threshold (NWR-T) have been part of clinical trials concerning the evaluation of the nociceptive system in the human body. NWR-T's are gathered by stimulation at the sole of the foot and over the sural pathway. Consequently, EMG analyzes the muscle activity over the biceps femoris and tibialis anterior muscle. Past studies favor stimulation at the sole of the foot.
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