STUDY DESIGN: A review of the literature regarding neurophysiologic mechanism of pain. OBJECTIVES: To review and discuss neurophysiologic mechanism of pain, including neuropathic pain. SUMMARY OF LITERATURE REVIEW: The neurophysiology of pain has been established at the cellular and molecular biology level through many studies. Also, multiple modalities to manage pain have been developed. MATERIALS AND METHODS: A literature review. RESULTS: Pain develops by actions of multiple receptors, ion channels and neurotransmitters along the pain pathway. Pathologic states, such as persistent pain, allodynia, and hyperalgesia, arise from alteration of the pain pathway. Especially, neuropathic pain results from nerve injury and its pathology is rather different from the neuroplasty of normal individuals. CONCLUSION: Multiple modalities, including individualized pain treatment based on pain phenotype, are introduced. However, optimal treatment is uncertain, therefore, further studies are needed.
Hyperalgesia ; Ion Channels ; Molecular Biology ; Neuralgia ; Neuronal Plasticity ; Neurophysiology ; Neurotransmitter Agents ; Pathology ; Phenotype

Sustained stress can have numerous pathologic effects. There have been several animal models for chronic stress. We tried to identify the changes of pain threshold and hippocampus in a model of chronic stress. Male Sprague-Dawley rats were kept in a cage filled with 23degrees C water to a height of 2.2 cm for 7 days. Nociceptive thresholds, expressed in grams, were measured with a Dynamic Plantar Aesthesiometer. Golgi staining was used to identify hippocampal changes. To demonstrate how long allodynia was lasting, behavioral test was repeated daily on another experiment. Compared to control group, chronic stress group showed bilateral mechanical hyper-responsiveness on days 5 (P = 0.047) and 7 (P = 0.032). In general, dendrite atrophic changes within hippocampus of chronic stress model were much more prominent in comparison with control. Compared to control, decreased spine number (P < 0.001) and spine length (P < 0.001) on Golgi staining were seen in the hippocampus of animals with chronic stress. Bilateral mechanical hyperresponsiveness was recovered on day 19 in animals with chronic stress. Chronic stress may bring about central sensitization and hippocampal changes in rats.
Animals ; Behavior, Animal ; Disease Models, Animal ; Hippocampus/*pathology ; Hyperalgesia/*pathology ; Male ; Pain Threshold ; Rats ; Rats, Sprague-Dawley ; Stress, Physiological

The cell body or soma in the dosal root ganglion (DRG) is normally excitable and this excitability can increase and persist after an injury of peripheral sensory neurons. In a rat model of radicular pain, an intraforaminal implantation of a rod that chronically compressed the lumbar DRG ("CCD" model) resulted in neuronal somal hyperexcitability and spontaneous activity that was accompanied by hyperalgesia in the ipsilateral hind paw. By the 5th day after onset of CCD, there was a novel upregulation in neuronal expression of the chemokine, monocyte chemoattractant protein-1 (MCP-1 or CCL2) and also its receptor, CCR2. The neurons developed, in response to topically applied MCP-1, an excitatory response that they normally do not have. CCD also activated non-neuronal cells including, for example, the endothelial cells as evidenced by angiogenesis in the form of an increased number of capillaries in the DRG after 7 days. A working hypothesis is that the CCD induced changes in neurons and non-neuronal cells that may act together to promote the survival of the injured tissue. The release of ligands such as CCL2, in addition to possibly activating nociceptive neurons (maintaining the pain), may also act to preserve injured cells in the face of ischemia and hypoxia, for example, by promoting angiogenesis. Thus, somal hyperexcitability, as often said of inflammation, may represent a double edged sword.
Animals ; Chemokine CCL2 ; metabolism ; Ganglia, Spinal ; cytology ; pathology ; Hyperalgesia ; pathology ; Neuroglia ; cytology ; Nociceptors ; cytology ; Pain ; pathology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Compression ; physiopathology ; Up-Regulation

OBJECTIVETo determine the effects of the autologous nucleus pulposus on the pain-related behaviors of hind paws in rats.

METHODSThe nucleus pulposus harvested from autologous coccygeal vertebra was applied beside the unilateral L4 and L5 nerve roots without compression. The mechanical withdrawal threshold of both paws were measured in different times after surgery. And hematoxylin and eosin (HE) staining was applied to observe the changes of nucleus pulposus and nerve roots.

RESULTSMechanical sensitivity of the operated side in paws obviously increased after application of autologous nucleus pulposus beside the lumbar nerve roots without compression. And HE staining showed obviously inflammatory changes in the nucleus pulposus and vacuolation in the nerve roots.

CONCLUSIONSInflammation resulted from nucleus pulposus may contribute to the development of mechanical hyperalgesia. The results suggest that in addition to mechanical compression, inflammation may be an important factor in the pathogenesis of sciatica.

Animals ; Disease Models, Animal ; Hyperalgesia ; etiology ; pathology ; physiopathology ; Intervertebral Disc Displacement ; complications ; pathology ; physiopathology ; Male ; Radiculopathy ; complications ; pathology ; physiopathology ; Rats ; Rats, Sprague-Dawley

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a^-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a^-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
Animals ; Mice ; Amputation, Surgical ; Chronic Pain/pathology* ; Disease Models, Animal ; Ganglia, Spinal/pathology* ; Hyperalgesia/etiology* ; Ion Channels/metabolism* ; Macrophages ; Neuroma/pathology*

To investigate the role of spinal interleukin-6-Janus kinase 2 (IL-6-JAK2) signaling transduction pathway in regulating astrocytes activation during the maintenance of bone cancer pain (BCP).
 Methods: NCTC 2472 fibrosarcoma cells were injected into the femur marrow cavity in C3H/HeNCrlVr male mice to establish BCP model and they were replaced by the equal volume of α-MEM in the sham model. The paw withdrawal latency (PWL) was measured after inoculation of tumor cells. The lumbar enlargement of spinal cord (L3-L5) was isolated, and Real-time RT-PCR and Western blot were used to detect the expression of spinal glial fibrillary acidic protein (GFAP) and JAK2 mRNA and protein, respectively. The expression level of spinal GFAP mRNA indirectly reflect astrocytes activation level. Pain behaviors and spinal cord GFAP mRNA and protein expression were observed at the given time points after intrathecal administration of JAK2 antagonist AG-490.
 Results: The PWL at 10, 14, 21 d after operation in BCP model group were significantly shorter than that in the sham group (P<0.05); the spinal GFAP and JAK2 mRNA and protein levels were higher in the BCP model group in comparison to mice in the sham group (P<0.05); intrathecal injection of JAK2 agonist AG-490 (30 or 90 nmol) significantly alleviated PWL, and downregulated the expression of spinal GFAP mRNA and protein (P<0.05).
 Conclusion: The IL-6-JAK2 signaling pathway plays an important role in maintaining the BCP by regulating the expression of GFAP in the spinal cord. Intrathecal injection of AG-490 can reduce the BCP, and inhibit the activation of IL-6-JAK2 signaling pathway, which may be one of the mechanisms for spinal astrocyte activation.
Animals ; Astrocytes ; pathology ; Bone Neoplasms ; complications ; Hyperalgesia ; drug therapy ; etiology ; Injections, Spinal ; Male ; Mice ; Mice, Inbred C3H ; Rats, Sprague-Dawley ; Spinal Cord ; cytology ; pathology ; Tyrphostins ; administration & dosage

Preoperative sleep loss can amplify post-operative mechanical hyperalgesia. However, the underlying mechanisms are still largely unknown. In the current study, rats were randomly allocated to a control group and an acute sleep deprivation (ASD) group which experienced 6 h ASD before surgery. Then the variations in cerebral function and activity were investigated with multi-modal techniques, such as nuclear magnetic resonance, functional magnetic resonance imaging, c-Fos immunofluorescence, and electrophysiology. The results indicated that ASD induced hyperalgesia, and the metabolic kinetics were remarkably decreased in the striatum and midbrain. The functional connectivity (FC) between the nucleus accumbens (NAc, a subregion of the ventral striatum) and the ventrolateral periaqueductal gray (vLPAG) was significantly reduced, and the c-Fos expression in the NAc and the vLPAG was suppressed. Furthermore, the electrophysiological recordings demonstrated that both the neuronal activity in the NAc and the vLPAG, and the coherence of the NAc-vLPAG were suppressed in both resting and task states. This study showed that neuronal activity in the NAc and the vLPAG were weakened and the FC between the NAc and the vLPAG was also suppressed in rats with ASD-induced hyperalgesia. This study highlights the importance of preoperative sleep management for surgical patients.
Rats ; Animals ; Hyperalgesia/metabolism* ; Sleep Deprivation/metabolism* ; Rats, Sprague-Dawley ; Periaqueductal Gray/pathology* ; Proto-Oncogene Proteins c-fos/metabolism* ; Pain, Postoperative/pathology*

Dorsal root ganglion (DRG) neurons have peripheral terminals in skin, muscle, and other peripheral tissues, and central terminals in the spinal cord dorsal horn. Hyperpolarization-activated current (I(h)) of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are present in the DRG. The genes encoding HCN channels have four subtypes named HCN1 to HCN4. HCN channels are permeable to both K(+) and Na(+). They underlie the depolarization that modulates the rhythmic generations of action potentials (APs), contribute to the resting membrane potential, and modify the waveform of propagated synaptic and generator potentials. Neuropathic pain is characterized by spontaneous pain, hyperalgesia and allodynia. After spinal nerve injury, the cell bodies of the primary sensory neurons in segmental DRG become hyperexcitable, characterized for some neurons by the presence of spontaneous firing (or ectopic discharge). In the following, we summarize our observations on the role of HCN channels in DRG neurons in neuropathic pain. 1 HCN subtypes and I(h) in DRG neurons Immunohistochemical staining revealed a subgroup of neurons in the DRG that were stained with rabbit polyclonal antibodies specific for HCN1, 2, 3 and 4. The most prominently expressed HCN subtype was HCN1. HCN1-positive cells in DRG were medium to large in size and doubly labeled with neurofilament-200 (NF-200), and were not labeled with isolectin B4 (IB4), a C fiber marker. In contrast, HCN2, 3 or 4 was expressed in all DRG neurons at a lower level. HCN4 was confined to small neurons. DRG neurons expressed I(h). When membrane was hyperpolarized, the channel was activated, mediating a slowly activated, inward current. I(h) was distributed mainly in large and medium-sized DRG neurons. 2 Changes in expression of HCN in DRG after spinal nerve ligation Western blotting was used to detect the changes in the expression of HCN subtypes in the DRG after spinal nerve ligation. HCN1 mRNA and protein were reduced in the DRG whose spinal nerve had been ligated. HCN1 expression was decreased to the lowest level at day 14 and restored at day 28 after spinal nerve ligation. HCN2 mRNA and medium molecular weight protein was also decreased in spinal-nerve ligated DRG. HCN3 and 4 in the same ganglion remained unchanged as evidenced by immunohistochemical staining, until day 28 when they became significantly decreased. HCN4 mRNA in DRG did not change, and protein expression slightly increased. Interestingly, abundant axonal accumulation of HCN channel protein at the injured sites in chronic constriction injury (CCI) rats. Electron immunomicroscopy showed strong positive immunolabeling on the axolemma of myelinated thick axons. 3 Role of I(h) in neuronal excitability and ectopic discharges after spinal nerve ligation ZD7288, a specific I(h) blocker, inhibited I(h) in a time- and concentration-dependent manner. With patch-clamp recording on acutely isolated DRG neurons, it was found that ZD7288 perfusion resulted in a decrease of both I(h) activity and the activation time constant. ZD7288 decreased the number of repetitive APs and caused an increase in AP rise time, accompanied by a small hyperpolarization of the membrane resting potential. The results demonstrated that I(h) was involved in AP firing, and possessed the physiological functions to facilitate neuronal excitability and ectopic firing. Extracellular electrophysiological recording from dorsal root fibers associated with the spinal nerve-ligated ganglion revealed three different firing patterns of ectopic discharges: tonic or regular, bursting and irregular. The average frequency of ectopic discharges and the proportions of active filaments also changed rapidly, both parameters reaching a peak within 24 h then declining gradually in the following days. It was also found that proportions of three different firing patterns changed dynamically over time. The tonic and bursting types were dominant patterns in the first 24 h, while the irregular became the only pattern at day 14. We found that all three firing patterns (tonic, bursting and irregular) were dose- and time-dependently inhibited by local application of ZD7288 to DRG. The rate of suppression was negatively related to the frequency of firing prior to the application of ZD7288. We also found that, while the tonic firing pattern was gradually transformed to bursting type by application of 100 mumol/L ZD7288, it could be transformed to integer multiples firing by 1000 mumol/L ZD7288. 4 Effects of administration of ZD7288 on mechanical allodynia after spinal nerve ligation or CCI After spinal nerve ligation, i.t. injection of 30 mug ZD7288 significantly increased the 50% paw withdrawal threshold, ipsilateral to the ligated nerve. ZD7288 had no effect if the dose was lower than 15 mug, but resulted in motor deficits if the dose was higher than 60 mug. ZD7288 produced much better effects in the early stage (5 or 14 days after spinal nerve ligation) than that in the late stage (28 days after spinal nerve ligation). In CCI rats, ZD7288 application to the injured sited also significantly suppressed the ectopic discharges from injured nerve fibers with no effect on impulse conduction. Moreover, mechanical allodynia was inhibited. In conclusion, these results demonstrated that I(h) participated in the development and maintenance of peripheral sensitivity associated with neuropathic pain and that it is a potential target for the design of novel analgesics in the future.
Action Potentials ; Animals ; Cyclic Nucleotide-Gated Cation Channels ; metabolism ; Ganglia, Spinal ; physiopathology ; Hyperalgesia ; physiopathology ; Membrane Potentials ; Nerve Fibers ; pathology ; Neuralgia ; physiopathology ; Neurons, Afferent ; pathology ; Rats ; Rats, Sprague-Dawley ; Spinal Nerves ; pathology

Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1 receptors, serotonin (5-hydrodytryptamine) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH.
Abdominal Pain ; Central Nervous System ; Gonadal Steroid Hormones ; Humans ; Hyperalgesia ; Hypersensitivity* ; Irritable Bowel Syndrome* ; Ligands ; Pain Perception ; Pathology ; Phosphotransferases ; Receptors, Adrenergic ; Receptors, Cannabinoid ; Receptors, Glutamate ; Receptors, Opioid ; Receptors, Proteinase-Activated ; Receptors, Serotonin ; Tachykinins ; Tyrosine ; Visceral Pain

OBJECTIVETo explore the effect of food allergy (FA) on the development of visceralgia sensibility and the substance P (SP) expression in colon of developing rats with FA.

METHODThree-week old female Sprague-Dawley (SD) rats were randomly divided into two groups (n = 10 in each). The rats in FA group were sensitized with ovalbumin (OVA) 40 µg and Al(OH)3 1 mg suspension solution (0.2 ml) intraperitoneal (i.p.) injection on day 0, only OVA 40 µg solution i.p. on day 2, 4, 7, 9, 11, respectively, and the rats were challenged by gavage with OVA solution 30 mg (2 ml) on day 20, 24, 28, 30. The rats in non-sensitized (NS) group were not challenged except handled in the same ways. The serum OVA-IgE were determined by enzyme-linked immuno sorbent assay (ELISA) on day 0, 30. Jejunum segments were used to observe morphological structure, the expression of eosinophils, and the density and the percentage of degranulation of mast cells (MC). The rats were appraised for the pain sensibility of intestinal tract under colorectal distension irritation by the electrophysiological method on external oblique in the 18-24 hr after the last challenge. Colons were used to analyze the expression of SP through immunohistochemical staining and computer image analyzing system.

RESULTThe serum OVA-IgE concentration and the eosinophils, mast cell, the percentage of mast cells degranulation in FA group were more than NS group (P < 0.01). The amplitudes of spike external oblique muscle of abdomen (EOMA, µV) of the FA group under the colorectal distension (CRD) pressures at 0, 15, 30, 45, 60, 75 mm Hg were (17.74 ± 0.72), (18.63 ± 1.72), (22.55 ± 1.70), (28.63 ± 7.00), (33.97 ± 7.34), (37.26 ± 8.40), and (17.43 ± 1.18), (17.27 ± 1.16), (17.73 ± 1.42), (19.55 ± 3.54), (23.29 ± 5.46), (25.20 ± 4.75) in NS group. With the CRD pressure increased, the amplitudes of spike EOMA increased significantly. There were significant differences between groups under the CRD pressures at 30, 45, 60, 75 mm Hg (F = 47.470, 13.367, 13.317, 15.390, P < 0.01). The expressions of colons SP in FA group and NS group are 247.12 ± 90.83 and 103.90 ± 58.94, respectively (t = 4.183, P < 0.01).

CONCLUSIONSensitization through i.p. pathway and challenge by gavage with OVA in early life could result in FA in young SD rats. FA in early life enabled the amplitudes of spike EOMA and the expression of colons SP increase significantly. It may be related to increase in amount and degranulation of MC and SP abnormal expression in colon, which could lead to the development of visceralgia sensibility.

Animals ; Colonic Diseases, Functional ; metabolism ; Disease Models, Animal ; Electrophysiology ; Female ; Food Hypersensitivity ; complications ; metabolism ; Hyperalgesia ; etiology ; metabolism ; physiopathology ; Intestinal Mucosa ; metabolism ; pathology ; Mast Cells ; metabolism ; Ovalbumin ; adverse effects ; Pain Threshold ; Rats ; Rats, Sprague-Dawley ; Stress, Psychological ; Substance P ; metabolism