As sciatica and low back pain are among the most common medical complaints, many studies have duplicated these conditions in animals. Chronic compression of the dorsal root ganglion （CCD） is one of these models. The...As sciatica and low back pain are among the most common medical complaints, many studies have duplicated these conditions in animals. Chronic compression of the dorsal root ganglion （CCD） is one of these models. The surgery is simple： after exposing the L4/L5 intervertebral foramina, stainless steel rods are implanted unilaterally, one rod for each vertebra, to chronically compress the lumbar dorsal root ganglion （DRG）. Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia - evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our un-derstanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG fa-cilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.展开更多
Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behaviora tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic p...Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behaviora tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic pain rats 3 28 days following model induction. The results of immunohistochemistry, western blot assays and reverse transcription-PCR showed that Nay1.7 protein and mRNA expression was significantly increased in the injured dorsal root ganglia. These findings indicated that Nay1.7 might play an important role in the model of chronic neuropathic pain展开更多
The use of iodine-125 （L251） in cancer treatment has been shown to relieve patients＇ pain. Consid- ering dorsal root ganglia are critical for neural transmission between the peripheral and central nervous systems, ...The use of iodine-125 （L251） in cancer treatment has been shown to relieve patients＇ pain. Consid- ering dorsal root ganglia are critical for neural transmission between the peripheral and central nervous systems, we assumed that 125I could be implanted into rat dorsal root ganglia to provide relief for neuropathic pain. 125I seeds with different radioactivity （0, 14.8, 29.6 MBq） were im- planted separately through L4-5 and L5-6 intervertebral foramen into the vicinity of the L5 dorsal root ganglion, von Frey hair results demonstrated the mechanical pain threshold was elevated after implanting 125I seeds from the high radioactivity group. Transmission electron microscopy revealed that nuclear membrane shrinkage, nucleolar margination, widespread mitochondrial swelling, partial vacuolization, lysosome increase, and partial endoplasmic reticulum dilation were visible at 1,440 hours in the low radioactivity group and at 336 hours in the high radio- activity group. Abundant nuclear membrane shrinkage, partial fuzzy nuclear membrane and endoplasmic reticulum necrosis were observed at 1,440 hours in the high radioactivity group. No significant difference in combined behavioral scores was detected between preoperation and postoperation in the low and high radioactivity groups. These results suggested that the mechan- ical pain threshold was elevated after implanting 125I seeds without influencing motor functions of the hind limb, although cell injury was present.展开更多
Along with the development of economy and society, type 2 diabetic mellitus(T2DM) has become one of the most common diseases at the global level. As one of the complications of T2 DM, diabetic neuropathic pain(DNP) st...Along with the development of economy and society, type 2 diabetic mellitus(T2DM) has become one of the most common diseases at the global level. As one of the complications of T2 DM, diabetic neuropathic pain(DNP) stubbornly and chronically affects the health and life of human beings. In the pain field, dorsal root ganglion(DRG) is generally considered as the first stage of the sensory pathway where the hyperexcitability of injured neurons is associated with different kinds of peripheral neuropathic pains. The abnormal electrophysiology is mainly due to the changed properties of voltage-gated sodium channels(VGSCs) and the increased sodium currents(INa). Curcumin is an active ingredient extracted from turmeric and has been demonstrated to ameliorate T2 DM and its various complications including DNP effectively. The present study demonstrates that the INa of small-sized DRG neurons are significantly increased with the abnormal electrophysiological characteristics of VGSCs in type 2 diabetic neuropathic pain rats. And these abnormalities can be ameliorated efficaciously by a period of treatment with curcumin.展开更多
Some pelvic pain syndromes are very resistant to medical treatment. Several studies have demonstrated that sacral neuromodulation, which has been successfully used for the treatment of bladder dysfunction, incontinenc...Some pelvic pain syndromes are very resistant to medical treatment. Several studies have demonstrated that sacral neuromodulation, which has been successfully used for the treatment of bladder dysfunction, incontinence, urinary retention and urinary frequency [1]-[3], can be successfully used for the treatment of chronic pelvic pain [4]-[7]. Several studies have also demonstrated significant involvement of dorsal column pathways in the transmission of visceral pelvic pain [8] and the successful use of spinal cord stimulation for the treatment of chronic pelvic pain [9]. We report three cases of severe chronic pelvic pain that failed conservative treatment modalities. Placement of a combined sacral nerve roots stimulator and a low thoracic spinal cord stimulator resulted in a significant pain relief and improvement in daily life activities. We believe that this combination may help patients suffering from chronic pelvic pain resistant to medical management.展开更多
Approximately 50-70% of patients experience incision-induced mechanical nociception after sur- gery. However, the mechanism underlying incision-induced mechanical nociception is still unclear. Interleukin-10 and brain...Approximately 50-70% of patients experience incision-induced mechanical nociception after sur- gery. However, the mechanism underlying incision-induced mechanical nociception is still unclear. Interleukin-10 and brain-derived neurotrophic factor are important pain mediators, but whether in- terleukin-10 and brain-derived neurotrophic factor are involved in incision-induced mechanical no- ciception remains uncertain. In this study, forty rats were divided randomly into the incision surgery （n = 32） and sham surgery （n = 8） groups. Plantar incision on the central part of left hind paw was performed under anesthesia in rats from the surgery group. Rats in the sham surgery group re- ceived anesthesia, but not an incision. Yon Frey test results showed that, compared with the sham surgery group, incision surgery decreased the withdrawal threshold of rats at 0.5, 3, 6 and 24 hours after incision. Immunofluorescence staining in the dorsal root ganglia of the spinal cord （L3-5） showed that interleukin-10 and brain-derived neurotrophic factor were expressed mainly on small- and medium-sized neurons （diameter 〈 20 pm and 20-40 pm） and satellite cells in the dorsal root ganglia of the spinal cord （L3-5） in the sham surgery group. By contrast, in the surgery group, high expression of interleukin-10 and brain-derived neurotrophic factor appeared in large-sized neurons （diameter 〉 40 pm） at 6 and 24 hours after incision surgery, which corresponded to the decreased mechanical withdrawal threshold of rats in the surgery group. These experimental findings suggest that expression pattern shift of interleukin-10 and brain-derived neurotrophic factor induced by inci- sion surgery in dorsal root ganglia of rats was closely involved in lowering the threshold to me- chanical stimulus in the hind paw following incision surgery. Pain-related mediators induced by in- cision surgery in dorsal root ganglia of rats possibly underlie mechanical nociception in ipsilateral hind paws.展开更多
BACKGROUND： Inflammatory responses in injured nerves have been recognized as important factors for initially sensitizing nociceptive neurons. Cyclooxygenase （COX） is the rate-limiting enzyme in prostaglandin synthe...BACKGROUND： Inflammatory responses in injured nerves have been recognized as important factors for initially sensitizing nociceptive neurons. Cyclooxygenase （COX） is the rate-limiting enzyme in prostaglandin synthesis, and COX-2 inhibitor is involved in mechanisms of analgesia and anti-inflammation. OBJECTIVE： To investigate the effects of COX-2 inhibitor on thermal and mechanical hyperalgesia, as well as expression of growth associated protein 43 （GAP-43） and nerve growth factor （NGF） in dorsal root ganglion, in a rat model of neuropathic pain due to chronic constriction injury. DESIGN, TIME AND SETTING： A randomized, controlled, comparison study that was performed at the Surgical Department and Pathological Laboratory, Second Affiliated Hospital of Shantou University Medical College from September 2006 to September 2007. MATERIALS： COX-2 inhibitor, Iornoxicam, was purchased from Nycomed Pharmaceutical （Austria）; rabbit anti-GAP-43, and rabbit anti-NGF polyclonal antibodies were purchased from Boster, Wuhan, China. METHODS： A total of 50 adult, Wistar rats were randomly assigned to four groups： normal control （n = 5）, model （n = 15）, normal saline control （n = 15）, and Iornoxicam treatment （n =15）. With exception of the control group, the sciatic nerve of all rats was loosely ligated to establish a model of chronic constriction injury. The model rats were divided into three subgroups according to varying post-operative survival periods： 3, 7 and 14 days （n = 5）, respectively. Rats in the Iornoxicam treatment group were intraperitoneally injected with 1.3 mg/kg lornoxicam every 12 hours throughout the entire experimental procedure. Rats in the normal saline control group were intraperitoneally injected with 1.3 mL/kg saline. MAIN OUTCOME MEASURES： Immunohistochemistry revealed expression of GAP-43 and NGF in the L5 dorsal root ganglions. Mechanical withdrawal threshold and thermal withdrawal latency were used to observe neurological behavioral changes in rats. RESULTS： The relative gray values of GAP-43- and NGF-positive neurons in the model group were remarkably increased compared with the normal control rats （P 〈 0.01）, while the relative gray values in the Iomoxicam treatment group were significantly less than the model and normal saline control groups （P 〈 0.01）. Mechanical withdrawal threshold and thermal withdrawal latency gradually decreased with increasing injury time in the model, normal saline control, and Iornoxicam treatment groups, and were significantly less than the normal control group （P 〈 0.05）. In addition, mechanical withdrawal threshold and thermal withdrawal latency were significantly greater in the Iornoxicam treatment group compared with the model and normal saline control groups （P 〈 0.05）. CONCLUSION： Intraperitoneal injection of the COX-2 inhibitor Iornoxicam attenuated mechanical and thermal hyperalgesia induced by sciatic nerve chronic constriction injury and inhibited the increased expression of GAP-43 and NGF.展开更多
Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in t...Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in the production and maintenance of hyperalgesia and allodynia.The present study was conducted to determine whether a relationship exists between estrogen and NMDAR1 in peripheral nerve pain.A chronic sciatic nerve constriction injury model of chronic neuropathic pain was established in rats.These rats were then subcutaneously injected with 17β-estradiol,the NMDAR1 antagonist D（-）-2-amino-5-phosphonopentanoic acid（AP-5）,or both once daily for 15 days.Compared with injured drug na？ve rats,rats with chronic sciatic nerve injury that were administered estradiol showed a lower paw withdrawal mechanical threshold and a shorter paw withdrawal thermal latency,indicating increased sensitivity to mechanical and thermal pain.Estrogen administration was also associated with increased expression of NMDAR1 immunoreactivity（as assessed by immunohistochemistry） and protein（as determined by western blot assay） in spinal dorsal root ganglia.This 17β-estradiol-induced increase in NMDAR1 expression was blocked by co-administration with AP-5,whereas AP-5 alone did not affect NMDAR1 expression.These results suggest that 17β-estradiol administration significantly reduced mechanical and thermal pain thresholds in rats with chronic constriction of the sciatic nerve,and that the mechanism for this increased sensitivity may be related to the upregulation of NMDAR1 expression in dorsal root ganglia.展开更多
Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained h...Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion （hDRG） tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Navl.7 （,-~ 50% of total Nav expression） and lower expres- sion of Navl.8 （~ 12%）, whereas the mouse DRG has higher expression of Nav 1.8 （- 45%） and lower expression of Navl.7 （- 18%）. To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel （0.1-1 μmol/L） for 24 h. Paclitaxel increased the Navl.7 but not Navl.8 expression and also increased the transient Na＋ currents and action potential firing frequency in small-diameter （〈50 ~tm） hDRG neurons. Thus, the hDRG provides a translational model in which to study ＂human pain in a dish＂ and test new pain therapeutics.展开更多
Summary： mRNAs of alpha-adrenoceptor （α-AR） subtypes are found in neurons in dorsal root ganglion （DRG） and change after peripheral nerve injury. In this study, the distribution of α-AR subtype proteins was stu...Summary： mRNAs of alpha-adrenoceptor （α-AR） subtypes are found in neurons in dorsal root ganglion （DRG） and change after peripheral nerve injury. In this study, the distribution of α-AR subtype proteins was studied in L5 DRG of normal rats and rats with chronic constriction injury of sciatic nerve （CCI）. Using immunofluorescence technique, it was found that α1A-, α1B-, and α2A-AR proteins were expressed in large, medium, and small size neurons in normal DRG, and significantly increased in all size neurons 14 days after CCI. α1D- and α2C-AR was also expressed in all size neurons in normal DRG. However, α1D-AR was significantly increased and α2C-AR was decreased in small size neurons 14 days post CCI. α2B-AR neurons were not detectable in normal and CCI DRG. Co-expression of α1A- and α2A-AR in the same neuron was observed in normal DRG and increased post CCI. Collectively, these results indicated that there is distinct distribution of α-AR subtypes in DRG neurons, and the distribution and levels of expression of α-AR subtypes change differently after CCI. The up-regulation of α-AR subtypes in DRG neurons may play an important role in the process of generating and transmitting neuropathic pain.展开更多
Chronic visceral hypersensitivity is an important type of chronic pain with unknown etiology and pathophysiology. Recent studies have shown that epigenetic regulation plays an important role in the development of chro...Chronic visceral hypersensitivity is an important type of chronic pain with unknown etiology and pathophysiology. Recent studies have shown that epigenetic regulation plays an important role in the development of chronic pain conditions. However, the role of mi RNA-325-5 p in chronic visceral pain remains unknown. The present study was designed to determine the roles and mechanism of mi RNA-325-5 p in a rat model of chronic visceral pain.This model was induced by neonatal colonic inflammation(NCI). In adulthood, NCI led to a significant reduction in the expression of mi RNA-325-5 p in colon-related dorsal root ganglia(DRGs), starting to decrease at the age of4 weeks and being maintained to 8 weeks. Intrathecal administration of mi RNA-325-5 p agomir significantly enhanced the colorectal distention(CRD) threshold in a time-dependent manner. NCI also markedly increased the expression of CCL2(C-C motif chemokine ligand 2) in colon-related DRGs at the m RNA and protein levels relative to age-matched control rats. The expression of CXCL12, IL33, SFRS7, and LGI1 was not significantlyaltered in NCI rats. CCL2 was co-expressed in Neu Npositive DRG neurons but not in glutamine synthetasepositive glial cells. Furthermore, CCL2 was mainly expressed in isolectin B4-binding-and calcitonin generelated peptide-positive DRG neurons but in few NF-200-positive cells. More importantly, CCL2 was expressed in mi R-325-5 p-positive DRG neurons. Intrathecal injection of mi RNA-325-5 p agomir remarkably reduced the upregulation of CCL2 in NCI rats. Administration of Bindarit, an inhibitor of CCL2, markedly raised the CRD threshold in NCI rats in a dose-and time-dependent manner. These data suggest that NCI suppresses mi RNA-325-5 p expression and enhances CCL2 expression, thus contributing to visceral hypersensitivity in adult rats.展开更多
Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA rece...Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA_1（also known as EDG2） and Na_v1.8 in the dorsal root ganglion（DRG） contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in na？ve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Na_v1.8expression in L_（4-6）DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Na_v1.8expression in ipsilateral L_（4-6）DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Na_v1.8 and LPA remarkably enhanced Na_v1.8 currents in DRG neurons, and this was blocked by either a protein kinase C（PKC） inhibitor or a PKCe inhibitor. Overall, we demonstrated the modulation of Na_v1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.展开更多
基金supported by the National Natural Science Foundation of China(30870829)
文摘As sciatica and low back pain are among the most common medical complaints, many studies have duplicated these conditions in animals. Chronic compression of the dorsal root ganglion （CCD） is one of these models. The surgery is simple： after exposing the L4/L5 intervertebral foramina, stainless steel rods are implanted unilaterally, one rod for each vertebra, to chronically compress the lumbar dorsal root ganglion （DRG）. Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia - evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our un-derstanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG fa-cilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.
基金This study was supported by the National Natural Science Foundation of China(The mechanism of Na_v 1.7 (encoded by SCN9A gene) activated by chronic neuropathic pain and the experimental study of analgesia by SCN9A RNAi), No.81171059
文摘Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behaviora tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic pain rats 3 28 days following model induction. The results of immunohistochemistry, western blot assays and reverse transcription-PCR showed that Nay1.7 protein and mRNA expression was significantly increased in the injured dorsal root ganglia. These findings indicated that Nay1.7 might play an important role in the model of chronic neuropathic pain
基金supported by Technology Foundation for Selected Overseas Chinese Scholar,Ministry of Personnel of China,2011,Ren 1144
文摘The use of iodine-125 （L251） in cancer treatment has been shown to relieve patients＇ pain. Consid- ering dorsal root ganglia are critical for neural transmission between the peripheral and central nervous systems, we assumed that 125I could be implanted into rat dorsal root ganglia to provide relief for neuropathic pain. 125I seeds with different radioactivity （0, 14.8, 29.6 MBq） were im- planted separately through L4-5 and L5-6 intervertebral foramen into the vicinity of the L5 dorsal root ganglion, von Frey hair results demonstrated the mechanical pain threshold was elevated after implanting 125I seeds from the high radioactivity group. Transmission electron microscopy revealed that nuclear membrane shrinkage, nucleolar margination, widespread mitochondrial swelling, partial vacuolization, lysosome increase, and partial endoplasmic reticulum dilation were visible at 1,440 hours in the low radioactivity group and at 336 hours in the high radio- activity group. Abundant nuclear membrane shrinkage, partial fuzzy nuclear membrane and endoplasmic reticulum necrosis were observed at 1,440 hours in the high radioactivity group. No significant difference in combined behavioral scores was detected between preoperation and postoperation in the low and high radioactivity groups. These results suggested that the mechan- ical pain threshold was elevated after implanting 125I seeds without influencing motor functions of the hind limb, although cell injury was present.
基金supported by a grant from the National Natural Science Foundation of China(No.81073125)Natural Science Foundation of Zhejiang Province(Y2090252)
文摘Along with the development of economy and society, type 2 diabetic mellitus(T2DM) has become one of the most common diseases at the global level. As one of the complications of T2 DM, diabetic neuropathic pain(DNP) stubbornly and chronically affects the health and life of human beings. In the pain field, dorsal root ganglion(DRG) is generally considered as the first stage of the sensory pathway where the hyperexcitability of injured neurons is associated with different kinds of peripheral neuropathic pains. The abnormal electrophysiology is mainly due to the changed properties of voltage-gated sodium channels(VGSCs) and the increased sodium currents(INa). Curcumin is an active ingredient extracted from turmeric and has been demonstrated to ameliorate T2 DM and its various complications including DNP effectively. The present study demonstrates that the INa of small-sized DRG neurons are significantly increased with the abnormal electrophysiological characteristics of VGSCs in type 2 diabetic neuropathic pain rats. And these abnormalities can be ameliorated efficaciously by a period of treatment with curcumin.
文摘Some pelvic pain syndromes are very resistant to medical treatment. Several studies have demonstrated that sacral neuromodulation, which has been successfully used for the treatment of bladder dysfunction, incontinence, urinary retention and urinary frequency [1]-[3], can be successfully used for the treatment of chronic pelvic pain [4]-[7]. Several studies have also demonstrated significant involvement of dorsal column pathways in the transmission of visceral pelvic pain [8] and the successful use of spinal cord stimulation for the treatment of chronic pelvic pain [9]. We report three cases of severe chronic pelvic pain that failed conservative treatment modalities. Placement of a combined sacral nerve roots stimulator and a low thoracic spinal cord stimulator resulted in a significant pain relief and improvement in daily life activities. We believe that this combination may help patients suffering from chronic pelvic pain resistant to medical management.
基金supported by the Science and Technology Project of Hunan Province,No.2010SK3119125 Talents Project of 3~(rd) Xiangya Hospital,Central South University in China
文摘Approximately 50-70% of patients experience incision-induced mechanical nociception after sur- gery. However, the mechanism underlying incision-induced mechanical nociception is still unclear. Interleukin-10 and brain-derived neurotrophic factor are important pain mediators, but whether in- terleukin-10 and brain-derived neurotrophic factor are involved in incision-induced mechanical no- ciception remains uncertain. In this study, forty rats were divided randomly into the incision surgery （n = 32） and sham surgery （n = 8） groups. Plantar incision on the central part of left hind paw was performed under anesthesia in rats from the surgery group. Rats in the sham surgery group re- ceived anesthesia, but not an incision. Yon Frey test results showed that, compared with the sham surgery group, incision surgery decreased the withdrawal threshold of rats at 0.5, 3, 6 and 24 hours after incision. Immunofluorescence staining in the dorsal root ganglia of the spinal cord （L3-5） showed that interleukin-10 and brain-derived neurotrophic factor were expressed mainly on small- and medium-sized neurons （diameter 〈 20 pm and 20-40 pm） and satellite cells in the dorsal root ganglia of the spinal cord （L3-5） in the sham surgery group. By contrast, in the surgery group, high expression of interleukin-10 and brain-derived neurotrophic factor appeared in large-sized neurons （diameter 〉 40 pm） at 6 and 24 hours after incision surgery, which corresponded to the decreased mechanical withdrawal threshold of rats in the surgery group. These experimental findings suggest that expression pattern shift of interleukin-10 and brain-derived neurotrophic factor induced by inci- sion surgery in dorsal root ganglia of rats was closely involved in lowering the threshold to me- chanical stimulus in the hind paw following incision surgery. Pain-related mediators induced by in- cision surgery in dorsal root ganglia of rats possibly underlie mechanical nociception in ipsilateral hind paws.
基金Supported by:the Scientific Research Program of Xiamen Science and Technology Bureau,No. 3502Z20077074
文摘BACKGROUND： Inflammatory responses in injured nerves have been recognized as important factors for initially sensitizing nociceptive neurons. Cyclooxygenase （COX） is the rate-limiting enzyme in prostaglandin synthesis, and COX-2 inhibitor is involved in mechanisms of analgesia and anti-inflammation. OBJECTIVE： To investigate the effects of COX-2 inhibitor on thermal and mechanical hyperalgesia, as well as expression of growth associated protein 43 （GAP-43） and nerve growth factor （NGF） in dorsal root ganglion, in a rat model of neuropathic pain due to chronic constriction injury. DESIGN, TIME AND SETTING： A randomized, controlled, comparison study that was performed at the Surgical Department and Pathological Laboratory, Second Affiliated Hospital of Shantou University Medical College from September 2006 to September 2007. MATERIALS： COX-2 inhibitor, Iornoxicam, was purchased from Nycomed Pharmaceutical （Austria）; rabbit anti-GAP-43, and rabbit anti-NGF polyclonal antibodies were purchased from Boster, Wuhan, China. METHODS： A total of 50 adult, Wistar rats were randomly assigned to four groups： normal control （n = 5）, model （n = 15）, normal saline control （n = 15）, and Iornoxicam treatment （n =15）. With exception of the control group, the sciatic nerve of all rats was loosely ligated to establish a model of chronic constriction injury. The model rats were divided into three subgroups according to varying post-operative survival periods： 3, 7 and 14 days （n = 5）, respectively. Rats in the Iornoxicam treatment group were intraperitoneally injected with 1.3 mg/kg lornoxicam every 12 hours throughout the entire experimental procedure. Rats in the normal saline control group were intraperitoneally injected with 1.3 mL/kg saline. MAIN OUTCOME MEASURES： Immunohistochemistry revealed expression of GAP-43 and NGF in the L5 dorsal root ganglions. Mechanical withdrawal threshold and thermal withdrawal latency were used to observe neurological behavioral changes in rats. RESULTS： The relative gray values of GAP-43- and NGF-positive neurons in the model group were remarkably increased compared with the normal control rats （P 〈 0.01）, while the relative gray values in the Iomoxicam treatment group were significantly less than the model and normal saline control groups （P 〈 0.01）. Mechanical withdrawal threshold and thermal withdrawal latency gradually decreased with increasing injury time in the model, normal saline control, and Iornoxicam treatment groups, and were significantly less than the normal control group （P 〈 0.05）. In addition, mechanical withdrawal threshold and thermal withdrawal latency were significantly greater in the Iornoxicam treatment group compared with the model and normal saline control groups （P 〈 0.05）. CONCLUSION： Intraperitoneal injection of the COX-2 inhibitor Iornoxicam attenuated mechanical and thermal hyperalgesia induced by sciatic nerve chronic constriction injury and inhibited the increased expression of GAP-43 and NGF.
基金supported by the Youth Shihezi University Applied Basic Research Project of China,No.2015ZRKYQ-LH19
文摘Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in the production and maintenance of hyperalgesia and allodynia.The present study was conducted to determine whether a relationship exists between estrogen and NMDAR1 in peripheral nerve pain.A chronic sciatic nerve constriction injury model of chronic neuropathic pain was established in rats.These rats were then subcutaneously injected with 17β-estradiol,the NMDAR1 antagonist D（-）-2-amino-5-phosphonopentanoic acid（AP-5）,or both once daily for 15 days.Compared with injured drug na？ve rats,rats with chronic sciatic nerve injury that were administered estradiol showed a lower paw withdrawal mechanical threshold and a shorter paw withdrawal thermal latency,indicating increased sensitivity to mechanical and thermal pain.Estrogen administration was also associated with increased expression of NMDAR1 immunoreactivity（as assessed by immunohistochemistry） and protein（as determined by western blot assay） in spinal dorsal root ganglia.This 17β-estradiol-induced increase in NMDAR1 expression was blocked by co-administration with AP-5,whereas AP-5 alone did not affect NMDAR1 expression.These results suggest that 17β-estradiol administration significantly reduced mechanical and thermal pain thresholds in rats with chronic constriction of the sciatic nerve,and that the mechanism for this increased sensitivity may be related to the upregulation of NMDAR1 expression in dorsal root ganglia.
基金supported in part by NIH RO1Grants NS87988,DE17794,and DE22743 to R.R.J and NS89479 to S.Y.L and R.R.J
文摘Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion （hDRG） tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Navl.7 （,-~ 50% of total Nav expression） and lower expres- sion of Navl.8 （~ 12%）, whereas the mouse DRG has higher expression of Nav 1.8 （- 45%） and lower expression of Navl.7 （- 18%）. To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel （0.1-1 μmol/L） for 24 h. Paclitaxel increased the Navl.7 but not Navl.8 expression and also increased the transient Na＋ currents and action potential firing frequency in small-diameter （〈50 ~tm） hDRG neurons. Thus, the hDRG provides a translational model in which to study ＂human pain in a dish＂ and test new pain therapeutics.
基金supported by grants from the National Natural Science Foundation of China(No.30160026)the Youth Science and Technology Innovation Special Foundation of Xinjiang Production and Construction Corps,China(No.2010JC33)
文摘Summary： mRNAs of alpha-adrenoceptor （α-AR） subtypes are found in neurons in dorsal root ganglion （DRG） and change after peripheral nerve injury. In this study, the distribution of α-AR subtype proteins was studied in L5 DRG of normal rats and rats with chronic constriction injury of sciatic nerve （CCI）. Using immunofluorescence technique, it was found that α1A-, α1B-, and α2A-AR proteins were expressed in large, medium, and small size neurons in normal DRG, and significantly increased in all size neurons 14 days after CCI. α1D- and α2C-AR was also expressed in all size neurons in normal DRG. However, α1D-AR was significantly increased and α2C-AR was decreased in small size neurons 14 days post CCI. α2B-AR neurons were not detectable in normal and CCI DRG. Co-expression of α1A- and α2A-AR in the same neuron was observed in normal DRG and increased post CCI. Collectively, these results indicated that there is distinct distribution of α-AR subtypes in DRG neurons, and the distribution and levels of expression of α-AR subtypes change differently after CCI. The up-regulation of α-AR subtypes in DRG neurons may play an important role in the process of generating and transmitting neuropathic pain.
基金supported by grants from the National Natural Science Foundation of China (81471137, 31730040, and 81771187)the Priority Academic Program Development of Jiangsu Higher Education Institutions of China
文摘Chronic visceral hypersensitivity is an important type of chronic pain with unknown etiology and pathophysiology. Recent studies have shown that epigenetic regulation plays an important role in the development of chronic pain conditions. However, the role of mi RNA-325-5 p in chronic visceral pain remains unknown. The present study was designed to determine the roles and mechanism of mi RNA-325-5 p in a rat model of chronic visceral pain.This model was induced by neonatal colonic inflammation(NCI). In adulthood, NCI led to a significant reduction in the expression of mi RNA-325-5 p in colon-related dorsal root ganglia(DRGs), starting to decrease at the age of4 weeks and being maintained to 8 weeks. Intrathecal administration of mi RNA-325-5 p agomir significantly enhanced the colorectal distention(CRD) threshold in a time-dependent manner. NCI also markedly increased the expression of CCL2(C-C motif chemokine ligand 2) in colon-related DRGs at the m RNA and protein levels relative to age-matched control rats. The expression of CXCL12, IL33, SFRS7, and LGI1 was not significantlyaltered in NCI rats. CCL2 was co-expressed in Neu Npositive DRG neurons but not in glutamine synthetasepositive glial cells. Furthermore, CCL2 was mainly expressed in isolectin B4-binding-and calcitonin generelated peptide-positive DRG neurons but in few NF-200-positive cells. More importantly, CCL2 was expressed in mi R-325-5 p-positive DRG neurons. Intrathecal injection of mi RNA-325-5 p agomir remarkably reduced the upregulation of CCL2 in NCI rats. Administration of Bindarit, an inhibitor of CCL2, markedly raised the CRD threshold in NCI rats in a dose-and time-dependent manner. These data suggest that NCI suppresses mi RNA-325-5 p expression and enhances CCL2 expression, thus contributing to visceral hypersensitivity in adult rats.
基金supported by the National Natural Science Foundation of China (81200854)the Natural Science Foundation of Jiangxi Province, China (20122BAB215027)+1 种基金the Science Foundation of the Educational Committee of Jiangxi Province, China (GJJ12064)the International Postdoctoral Exchange Fellowship Program, China (20150062)
文摘Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA_1（also known as EDG2） and Na_v1.8 in the dorsal root ganglion（DRG） contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in na？ve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Na_v1.8expression in L_（4-6）DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Na_v1.8expression in ipsilateral L_（4-6）DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Na_v1.8 and LPA remarkably enhanced Na_v1.8 currents in DRG neurons, and this was blocked by either a protein kinase C（PKC） inhibitor or a PKCe inhibitor. Overall, we demonstrated the modulation of Na_v1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.
