Glycosides for Peripheral Neuropathic Pain: A Potential Medicinal Components

Neuropathic pain is a refractory disease that occurs across the world and pharmacotherapy has limited efficacy and/or safety. This disease imposes a significant burden on both the somatic and mental health of patients; indeed, some patients have referred to neuropathic pain as being ‘worse than death’. The pharmacological agents that are used to treat neuropathic pain at present can produce mild effects in certain patients, and induce many adverse reactions, such as sedation, dizziness, vomiting, and peripheral oedema. Therefore, there is an urgent need to discover novel drugs that are safer and more effective. Natural compounds from medical plants have become potential sources of analgesics, and evidence has shown that glycosides alleviated neuropathic pain via regulating oxidative stress, transcriptional regulation, ion channels, membrane receptors and so on. In this review, we summarize the epidemiology of neuropathic pain and the existing therapeutic drugs used for disease prevention and treatment. We also demonstrate how glycosides exhibit an antinociceptive effect on neuropathic pain in laboratory research and describe the antinociceptive mechanisms involved to facilitate the discovery of new drugs to improve the quality of life of patients experiencing neuropathic pain.

Enhanced Pronociceptive and Disrupted Antinociceptive Mechanisms in Nonspecific Chronic Neck Pain

Objective Evidence suggests altered pronociceptive and antinociceptive mechanisms in many chronic pain conditions. Knowledge about these mechanisms in nonspecific chronic neck pain (NSNP) would improve understanding of the causes and the design of more effective treatments. Pressure pain threshold (PPT) is often used to assess presence of altered nociceptive processing in NSNP; however, its usefulness to detect this is yet to be established. The purpose of this study was to determine the functional status of temporal summation of second pain (TSSP) and conditioned pain modulation (CPM) in NSNP and to characterize the association of both measures with PPT and clinical features of NSNP. Methods Thirty-two participants with NSNP (mean [SD] age = 44 [11] y; 27 female) and 32 age and sex matched healthy controls were recruited. TSSP was assessed using an electrical stimulus at the dorsum of the hand, and CPM was evaluated with the Cold Pressor Test. PPT was assessed bilaterally at the neck and tibialis anterior muscles. Results Participants with NSNP showed greater TSPP (mean difference = 0.23; 95% CI = 0.46-0.01; Cohen d = 0.51) and lower CPM (mean difference = 19.44; 95% CI = 10.42-28.46; Cohen d = 1.09). Pooled data from all participants showed lower PPTs at the neck than the tibialis anterior. However, PPT measures did not differ between groups at either location. PPT measures were not correlated with CPM and TSP. Conclusion NSNP is associated with enhanced pronociceptive and impaired antinociceptive mechanisms, which may explain long-lasting pain and failure of some treatments to resolve symptoms. However, due to the observational nature of this study, a clear cause-effect relationship cannot be established. Normal PPT values in the clinic should not be interpreted as absence of altered nociceptive processing. Impact This study fills in some gaps in knowledge. Changes in central nociceptive processing may explain persistent and recurrent symptoms in NSNP and failure of treatments to obtain long-lasting relief. Further research is required to ascertain if TSSP and CPM assessment in the clinic may help predict physical therapy treatment outcome. Whether symptomatic relief with physical therapy is mediated by an improvement in TSSP and CPM should also be explored. PPTs were unaltered in participants with NSNP despite evidence of impairment in the central pain modulatory systems. Normal PPTs should not be interpreted as evidence of unaltered central pain-related processing.

Tension-type headache

Tension-type headache (TTH) is usually a dull, bilateral headache without accompanying symptoms. It is divided into three subtypes: infrequent episodic TTH (< 1 headache day per month), frequent episodic TTH (1–14 headache days per month), and chronic TTH (≥ 15 headache days per month). This division is highly relevant for three reasons. Firstly, impact on quality of life differs considerably between the three subtypes. Secondly, the pathophysiological mechanisms also differ. Peripheral mechanisms such as muscle tension are more important in episodic TTH, whereas central pain sensitization with reduced antinociceptive mechanisms are pivotal in chronic TTH. Thirdly, treatment differs between the subtypes, with symptomatic and prophylactic treatment being more appropriate for episodic and chronic TTH, respectively. Non-pharmacological management should always be part of the treatment. Patients with episodic TTH are treated with analgesics, while prophylactic drugs (in particular antidepressants) should be considered in patients with very frequent episodic or chronic TTH.

Cellular Mechanisms for Antinociception Produced by Oxytocin and Orexins in the Rat Spinal Lamina II—Comparison with Those of Other Endogenous Pain Modulators

Much evidence indicates that hypothalamus-derived neuropeptides, oxytocin, orexins A and B, inhibit nociceptive transmission in the rat spinal dorsal horn. In order to unveil cellular mechanisms for this antinociception, the effects of the neuropeptides on synaptic transmission were examined in spinal lamina II neurons that play a crucial role in antinociception produced by various analgesics by using the whole-cell patch-clamp technique and adult rat spinal cord slices. Oxytocin had no effect on glutamatergic excitatory transmission while producing a membrane depolarization, γ-aminobutyric acid (GABA)-ergic and glycinergic spontaneous inhibitory transmission enhancement. On the other hand, orexins A and B produced a membrane depolarization and/or a presynaptic spontaneous excitatory transmission enhancement. Like oxytocin, orexin A enhanced both GABAergic and glycinergic transmission, whereas orexin B facilitated glycinergic but not GABAergic transmission. These inhibitory transmission enhancements were due to action potential production. Oxytocin, orexins A and B activities were mediated by oxytocin, orexin-1 and orexin-2 receptors, respectively. This review article will mention cellular mechanisms for antinociception produced by oxytocin, orexins A and B, and discuss similarity and difference in antinociceptive mechanisms among the hypothalamic neuropeptides and other endogenous pain modulators (opioids, nociceptin, adenosine, adenosine 5’-triphosphate (ATP), noradrenaline, serotonin, dopamine, somatostatin, cannabinoids, galanin, substance P, bradykinin, neuropeptide Y and acetylcholine) exhibiting a change in membrane potential, excitatory or inhibitory transmission in the spinal lamina II neurons.

Antinociceptive Activity of Petroleum Ether Fraction of Clinacanthus nutans Leaves Methanolic Extract: Roles of Nonopioid Pain Modulatory Systems and Potassium Channels

Methanolic extract of Clinacanthus nutans Lindau leaves (MECN) has been reported to exert antinociceptive activity. The present study aimed to elucidate the possible antinociceptive mechanisms of a lipid-soluble fraction of MECN, which was obtained after sequential extraction in petroleum ether. The petroleum ether fraction of C. nutans (PECN), administered orally to mice, was (i) subjected to capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged (intraperitoneal (i.p.)) with 0.15 mg/kg yohimbine, 1 mg/kg pindolol, 3 mg/kg caffeine, 0.2 mg/kg haloperidol, or 10 mg/kg atropine, which were the respective antagonist of α2-adrenergic, β-adrenergic, adenosinergic, dopaminergic, or muscarinic receptors; and (iii) prechallenged (i.p.) with 10 mg/kg glibenclamide, 0.04 mg/kg apamin, 0.02 mg/kg charybdotoxin, or 4 mg/kg tetraethylammonium chloride, which were the respective inhibitor of ATP sensitive-, small conductance Ca2+-activated-, large conductance Ca2+-activated-, or nonselective voltage-activated-K+ channel. Results obtained demonstrated that PECN (100, 250, and 500 mg/kg) significantly (P<0.05) inhibited all models of nociception described earlier. The antinociceptive activity of 500 mg/kg PECN was significantly (P<0.05) attenuated when prechallenged with all antagonists or K+ channel blockers. However, only pretreatment with apamin and charybdotoxin caused full inhibition of PECN-induced antinociception. The rest of the K+ channel blockers and all antagonists caused only partial inhibition of PECN antinociception, respectively. Analyses on PECN’s phytoconstituents revealed the presence of antinociceptive-bearing bioactive compounds of volatile (i.e., derivatives of γ–tocopherol, α–tocopherol, and lupeol) and nonvolatile (i.e., cinnamic acid) nature. In conclusion, PECN exerts a non-opioid-mediated antinociceptive activity involving mainly activation of adenosinergic and cholinergic receptors or small- and large-conductance Ca2+-activated-K+ channels.

MULTIPLE SCLEROSIS. JUSTIFICATION OF GEROPROTECTIVE THERAPY

Results of immunological blood count and liquor test taken from 76 patients with multiple sclerosis aged 33,6±2,7 were studied to determine genetic markers of locus HLA-drB1and asynchronous intrathecal synthesis ratio of immunoglobulin free light chain (К ƙ/ƛ), as well as state of mitochondrial electron transport chain and density of neurotransmitter receptors of brain cells. 12 laboratory Guinea pigs with experimental allergic encephalomyelitis were taken to conduct electron microscopy of ultrathin brain sections collected from animals at the peak of the disease. Weak association of immunological and genetic indicators and statistically significant morphofunctional abnormalities of mitochondrial appara- tus of brain cells as well as neurotransmitter deviations towards nociceptive processes with simultaneous weakening of central antinociceptive mechanisms was found. The conclusion is that patients with mul- tiple sclerosis have early pathologic aging so early geroprotective therapy is required.