Regulation Of Pain Perception Research Articles

Regulation of pain perception by microbiota in Parkinson's Disease.

Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T-cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons affecting their excitability, or indirectly on non-neuronal cells inducing changes in the production of pro-inflammatory or anti-inflammatory mediators. Importantly, Parkinson's disease, a neurodegenerative and inflammatory disorder that affect mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also non-motor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson's disease involves a dysbiosis in the composition of the gut microbiota. In this review, first, we summarize, integrate and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Secondly, we analyze the changes on the commensal microbiota associated to Parkinson's disease and propose how these changes affect the development of chronic pain in this pathology. Significance Statement The microbiota regulates chronic-pain through the action of bacterial signals into two main locations: the peripheral nociceptors and the postsynaptic excitatory neurons in the spinal cord. The dysbiosis associated to Parkinson's disease reveals increased representation of commensals that potentially exacerbate chronic pain and reduced levels of bacteria with beneficial effects on pain. This review encourages further research to better understand the signals involved in bacteria-bacteria and bacteria-host communication to get the clues for the development of probiotics with therapeutic potential.

Prokineticin 2 mediates peripheral and central sensitization of somatic pain

Prokineticin 2 (PK2) is a newly discovered chemokine, which participates in various physiological functions of the body by binding to receptors PKR1 and PKR2. PK signaling pathway is a newly discovered important regulatory pathway for the occurrence and maintenance of pain after tissue injury and nerve injury in recent years. It plays a key role in regulating injury-related nociceptive events and is a potential therapeutic target for many diseases. The activation of PKRs can induce pain sensation and participate in the sensitivity of pain receptors to different stimuli. The PK system (PKs and PKRs) is an important link involved in inflammation and pain transmission in immune cells. PK2 is involved in the regulation of pain perception by activating PKR1 and PKR2 on primary sensory neurons. In rat primary sensory neurons, PK2 also enhances gated ion channel current through the PKC signaling pathway, inhibits GABA-activated currents, and sensitizes purine nucleotide P2 receptor (P2X). This paper reviews the research progress of PK2 in physical pain. We hope to find new drugs for the treatment of inflammatory pain that target the PKs signaling pathway in future studies.

P28. Sympathetic activity in patients with fibromyalgia – A microneurographic study

Introduction Fibromyalgia is a disease which is characterized by -“widespread pain”-, one aspect of the pathophysiology might be a central dysregulation of autonomic as well as endocrine parameters. The baroreflexsensitivity (BRS) is being discussed as a connecting link. The nucleus tractus solitarii (NTS) was identified as a crucial structure of the BRS which is important for the regulation of sympathetic functions such as blood pressure and heart frequency but also for the central regulation of pain perception. The physiological state of an inverse relation between blood pressure and pain perception is diminished in patients with fibromyalgia. An efferent arm of the baroreflex is the vasoconstrictor activity of the muscle vessels (MSNA; muscle-sympathetic-nerve-activity) which can be directly assessed by the method of microneurography. The aim of this study was to detect differences of sympathetic activity between fibromyalgia patient and healthy controls by directly measuring the sympathetic outflow using the method of microneurography. Methods MSNA was obtained from 12 patients with fibromyalgia and 11 healthy controls. MSNA was recorded from the peroneal nerve during rest (baseline) and during baroreflex-stimulation by lower-body-negative-pressure (LBNP, −40 mmHg). Analyzed were burst frequency (burst per minute) and burst incidence (burst per hundred heart beats) as well as the autonomic parameters as blood pressure, heart rate variability and baroreflexsensitivity. Results The microneurographic data shows that the burst frequency of fibromyalgia patients is a higher in the baseline ( T = 2.675, p = 0.014) and during LBNP ( F = 5.571, p = 0.03) compared to the healthy controls, the same tendency was visible for burst incidence but level of significance was not reached. The relative increase in BF and BI by LBNP did not differ between the FM-patients and controls. The other autonomic parameters showed a decreased baroreflexsensitivity and increased blood pressure in FM patients compared to controls. Analysis of heart rate variability revealed decresed vagal activity in FM patients. Conclusion So far our results show an autonomic dysbalance with a higher sympathetic activity in the FM-patients compared to the healthy volunteers. The higher outflow of sympathetic activity may play a vital role in the pathophysiological mechanisms of developing fibromyalgia.

The zebrafish as a model for nociception studies

Nociception is the sensory mechanism used to detect cues that can harm an organism. The understanding of the neural networks and molecular controls of the reception of pain remains an ongoing challenge for biologists. While we have made significant progress in identifying a number of molecules and pathways that are involved in transduction of noxious stimuli, from the skin through the sensory receptor cell and from this to the spinal cord on into the central nervous system, we still lack a clear understanding of the perceptual processes, the responses to pain and the regulation of pain perception. Mice and rat animal models have been extensively used for nociception studies. However, the study of pain and noiception in these organisms can be rather laborious, costly and time consuming. Conversely, the use of Drosophila and Caenorhabditis elegans may be affected by the large evolutionary distance between these animals and humans. We outline here the reasons why zebrafish presents a new and attractive model for studying pain reception and responses and the most interesting findings in the study of nociception that have been obtained using the zebrafish model.

Pharmacogenetics of Chronic Pain and Its Treatment

This paper reviews the impact of genetic variability of drug metabolizing enzymes, transporters, receptors, and pathways involved in chronic pain perception on the efficacy and safety of analgesics and other drugs used for chronic pain treatment. Several candidate genes have been identified in the literature, while there is usually only limited clinical evidence substantiating for the penetration of the testing for these candidate biomarkers into the clinical practice. Further, the pain-perception regulation and modulation are still not fully understood, and thus more complex knowledge of genetic and epigenetic background for analgesia will be needed prior to the clinical use of the candidate genetic biomarkers.

Mediators of Inflammation as Targets for Chronic Pain Treatment

Mediators of Inflammation as Targets for Chronic Pain Treatment

Effects of heroin on regulation of painful perception in hippocampus neurons of rat

Objective The heroin-dependent animal model of rats was used to investigate the effects of heroin on regulation of pain perception in the dorsal and ventral hippocampus of the heroin-dependent rats. Meth ods Heroin was injected subcutaneously twice a lay for 9 days according to the principle of daily increasing dose in the Sprague-Dawley rats. From the 10th day,rats were given heroin at dose of 27 mg · kg-1 once a day until the 14th day, then the unit discharges of the dorsal and ventral hippocampus of rats were observed respectively after noxious electric stimulation of the rat-tail by the extracellular single-unit recording with glass microelectrodes. Results When given noxious stimulation, most of the neurons in the dorsal hippocampus in the heroin-dependent rats were unaffected(59.09％ ) ,whereas in the control rats ,the ratio of the neurons of the dorsal hippocampus affected by noxious stimulation was about 66.67％, respectively(P ＜ 0.05 ). However,in the ventral hippocampus, the ratio of the neurons activated,inhibitory or unaffected was 20. 69％ ,41.38％ and 37.93％ from the control and was 40.74％ ,33. 33％ and 25.93％ from the heroin group respectively with no significant difference between two groups (P ＞ 0.05 ) . Conclusion Heroin changed the regulation of pain perception in the hippocampus,primarily the dorsal hippocampus of rats. Key words: Heroin; Hippocampus; Unit discharge; Pain; Electric stimulation

Effect of acetylcholine on pain-related electric activities in hippocampal CA1 area of normal and morphinistic rats

To examine the effect of acetylcholine (ACh) on the electric activities of pain-excitation neurons (PEN) and pain-inhibitation neurons (PIN) in the hippocampal CA1 area of normal rats or morphinistic rats, and to explore the role of ACh in regulation of pain perception in CA1 area under normal condition and morphine addiction. The trains of electric impulses applied to sciatic nerve were set as noxious stimulation. The discharges of PEN and PIN in the CA1 area were recorded extracellularly by glass microelectrode. We observed the influence of intracerebroventricular (i.c.v.) injection of ACh and atropine on the noxious stimulation-evoked activities of PEN and PIN in the CA1 area. Noxious stimulation enhanced the electric activity of PEN and depressed that of PIN in the CA1 area of both normal and addiction rats. In normal rats, ACh decrease the pain-evoked discharge frequency of PEN, while increased the frequency of PIN. These effects reached the peak value at 4 min after injection of ACh. In morphinistic rats, ACh also inhibited the PEN electric activity and potentialized the PIN electric activity, but the maximum effect appeared at 6 min after administration. The ACh-induced responses were significantly blocked by muscarinic receptor antagonist atropine. Cholinergic neurons and muscarinic receptors in the hippocampal CA1 area are involved in the processing of nociceptive information and they may play an analgesia role in pain modulation. Morphine addiction attenuated the sensitivity of pain-related neurons to the noxious information.

Naloxone‐induced abdominal distress in the horse

Endogenous opioid peptides have been implicated in the regulation of pain perception, behaviour, gastrointestinal activity and other physiological responses. However, the functional role of these peptides in the horse has yet to be elucidated. The opioid antagonist, naloxone, is often administered to infer endogenous opioid effects. In the present study, naloxone (0.75 mg/kg bodyweight) was administered to eight Thoroughbred racehorses and a number of behavioural and autonomic responses were measured. Naloxone produced rapid onset diarrhoea, restlessness, abdominal checking, tachycardia, tachypnoea, paradoxical yawning and diaphoresis. These responses described an acute abdominal distress syndrome similar to spasmodic colic. Results from this study suggest that, in the horse, endogenous opioids: 1) influence behaviour, 2) modify intestinal activity and sensation, and 3) if perturbed, may be involved in pathophysiology of colic.

The ascent of cholecystokinin (CCK) — From gut to brain

Cholecystokinin (CCK), a classical gastrointestinal polypeptide hormone, appears to have an equally important role as a brain neurotransmitter. CCK is widely distributed throughout both the central and peripheral nervous system. Of the known brain peptides, only CCK and VIP are predominately cerebral cortical peptides. In the pituitary, CCK is found in the posterior pituitary, while gastrin-like peptides are present in the anterior and intermediate lobes. Phylogenetically, gastrin-CCK-like peptides arose extremely early in evolution being present in the primitive nerve cells of the coelenterate, Hydra. Specific high affinity CCK-receptors have been demonstrated in rat and guinea-pig brains with highest concentrations in the cerebral cortex, caudate nucleus and olfactory bulb. Alterations in CCK binding have been reported during fasting and in genetically obese rats and mice. The low levels of CCK receptors in patients with Huntington's Chorea, the coexistance of CCK with dopamine in the same mesolimbic neurons and the rotational syndrome produced after central administration in rats suggests a potential physiological role for CCK in the regulation of extra-pyramidal function. CCK and/or gastrin have been demonstrated to have a number of effects on anterior pituitary hormones and the high concentrations in the posterior pituitary suggest a possible neuromodulatory role in the regulation of vasopressin and/or oxytocin release. CCK is a putative satiety hormone which appears to produce satiety both by peripheral and central effects. The presence of CCK in the periaqueductal gray and the fact that it produces naloxone reversible analgesia suggest a potential role for CCK in the regulation of pain perception. Central administration of CCK produces hyperglycemia which appears to be partly mediated via an adrenal mechanism. CCK also produces mild hypothermia and appears to be a central nervous system depressant. Present evidence indicating that CCK is a central neurotransmitter or neuromodulator includes its regional distribution with localization within neuronal cell bodies and axons; the demonstration that it can be synthesized in neuronal tissue; the fact that it is released by depolarizing stimuli in vitro ; the presence of specific, high affinity receptors for CCK in the brain; and the finding that it can activate isolated neurons. The high concentrations of CCK in the cerebral cortex suggest that future studies will produce further surprises concerning the physiological role of this gall-bladder contracting hormone which came of age with the discovery of its wide distribution in the central nervous system.

Naloxone alters pain perception and somatosensory evoked potentials in normal subjects : M.S. Buchsbaum, G.C. Davis and W.E. Bunney, Nature (Lond.), 270 (1977) 620–622

THE discovery of opiate-like peptides (endorphins) in brain, blood and cerebrospinal fluid1–4 raises questions as to the physiological role of these substances. Given the prominent analgesic effects of opiates, the regulation of pain perception is a candidate for endorphin action. Endorphins microinjected into the periacqueductal grey matter of rats induce analgesia which is reversed by naloxone, a pure narcotic antagonist5. If endorphins play an active part in the regulation of pain, then naloxone administered to man should alter pain appreciation. Naloxone has not been shown to have analgesic, respiratory, euphoric, pupillary or electroencephalogram (EEG) effects in man6. Studies in rats7,8 and one early study in man9 have suggested slight hyperalgesic effects with naloxone. El-Sobky et al.10 failed to demonstrate naloxone effects on electric shock pain judgments in five subjects. In the experiments reported here, subjects were divided into pain sensitive and pain insensitive subgroups. The insensitive subjects found shocks significantly more painful after naloxone administration while the sensitive group experienced them as less painful. Evoked potentials showed similar significant group differences. These results suggest that individual differences in pain sensitivity may relate to differences in an endorphin system.

Naloxone alters pain perception and somatosensory evoked potentials in normal subjects

THE discovery of opiate-like peptides (endorphins) in brain, blood and cerebrospinal fluid1–4 raises questions as to the physiological role of these substances. Given the prominent analgesic effects of opiates, the regulation of pain perception is a candidate for endorphin action. Endorphins microinjected into the periacqueductal grey matter of rats induce analgesia which is reversed by naloxone, a pure narcotic antagonist5. If endorphins play an active part in the regulation of pain, then naloxone administered to man should alter pain appreciation. Naloxone has not been shown to have analgesic, respiratory, euphoric, pupillary or electroencephalogram (EEG) effects in man6. Studies in rats7,8 and one early study in man9 have suggested slight hyperalgesic effects with naloxone. El-Sobky et al.10 failed to demonstrate naloxone effects on electric shock pain judgments in five subjects. In the experiments reported here, subjects were divided into pain sensitive and pain insensitive subgroups. The insensitive subjects found shocks significantly more painful after naloxone administration while the sensitive group experienced them as less painful. Evoked potentials showed similar significant group differences. These results suggest that individual differences in pain sensitivity may relate to differences in an endorphin system.