Excitatory toxicity(ET) is an important factor of neuropathic pain(NPP) induced by central sensitization(CS), and the association of pannexin-1(Panx1)-Src-N-methyl-D-aspartate receptor subunit 2 B(NMDAR-2 B) is an important new pathway for ET to initiate CS. The present study confirmed whether the central analgesic effect of Chuanxiong Rhizoma extract(CRE) was achieved through the synchronous regulation of the brain and spinal pathways of Panx1-Src-NMDAR-2 B. In this study, dynamic and simulta-neo-us microdialysis of the brain and spinal cord in vivo combined with behavioristics, high performance liquid chromatography(HPLC)-fluorescence detection, microdialysis analysis(ISCUS~(flex)), ultrasensitive multifactorial electrochemiluminescence immunoassay, ELISA, and Western blot was employed to investigate the protein expression of NMDAR-2 B, Src, and Panx1, extracellular excitatory amino acids, cytokines, energy metabolites, and substance P in spinal dorsal horn(SDH) and anterior cingulate cortex(ACC) after CRE intervention with the rat model of spared sciatic nerve injury(SNI) as the experimental tool. Compared with the sham group, the SNI group exhibited diminished mechanical withdrawal threshold(MWT)(P<0.01), increased cold spray scores(P<0.01), glutamate(Glu), D-serine(D-Ser), and glycine(Gly) in extracellular fluids of ACC, and Glu, D-Ser, interleukin-1β(IL-1β), and lactic acid(Lac) in extracellular fluids of SDH(P<0.05), dwindled tumor necrosis factor(TNF-α)(P<0.05), and elevated protein levels of NMDAR-2 B, Src, and Panx1 in ACC(P<0.05). Compared with the SNI model rats, high-and medium-dose CRE(CRE-H/M) could potentiate the analgesic activity as revealed by the MWT test(P<0.05) and CRE-M enabled the decrease in cold spray scores(P<0.05). CRE-H/M could inhibit the levels of Glu, D-Ser and Gly in the extracellular fluids of ACC(P<0.05), and the levels of Glu in the extracellular fluids of SDH(P<0.05) in SNI rats. CRE-M significantly increased the levels of glucose(Gluc), Lac, interferon-gamma(IFN-γ), keratinocyte chemoattractant/human growth-regulated oncogenes(KC/GRO), and IL-4 in extracellular fluids of SDH in SNI rats(P<0.05). CRE-H/M/L could also inhibit the levels of NMDAR-2 B, Src and Panx1 in ACC and SDH in SNI rats(P<0.05). The central analgesic effect of CRE is presumedly related to the inhibited release of excitatory amino acid transmitters(Glu, D-Ser and Gly) in ACC and SDH of SNI rats, decreased protein expression of NMDAR-2 B, Src and Panx1 in the two regions, and the regulation of the Panx1-Src-NMDAR-2 B pathway in the spinal cord and brain. The above findings partially clarified the scientific basis of clinical analgesic effect of Chuanxiong Rhizoma.
Animals ; Central Nervous System Sensitization ; Neuralgia/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Signal Transduction ; Spinal Cord/metabolism*

We have previously demonstrated that the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces functional potentiation of N-methyl-D-aspartate (NMDA) receptors via increases in phosphorylation of NMDA receptor GluN1 subunit (pGluN1). However, the modulatory mechanisms responsible for the expression of the DHEA-synthesizing enzyme, cytochrome P450c17 following peripheral nerve injury have yet to be examined. Here we determined whether oxidative stress induced by the spinal activation of nitric oxide synthase type II (NOS-II) modulates the expression of P450c17 and whether this process contributes to the development of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of NOS-II in microglial cells and NO levels in the lumbar spinal cord dorsal horn at postoperative day 5. Intrathecal administration of the NOS-II inhibitor, L-NIL during the induction phase of neuropathic pain (postoperative days 0~5) significantly reduced the CCI-induced development of mechanical allodynia and thermal hyperalgesia. Sciatic nerve injury increased the expression of PKC- and PKA-dependent pGluN1 as well as the mRNA and protein levels of P450c17 in the spinal cord at postoperative day 5, and these increases were suppressed by repeated administration of L-NIL. Co-administration of DHEAS together with L-NIL restored the development of neuropathic pain and pGluN1 that were originally inhibited by L-NIL administration alone. Collectively these results provide strong support for the hypothesis that activation of NOS-II increases the mRNA and protein levels of P450c17 in the spinal cord, ultimately leading to the development of central sensitization and neuropathic pain induced by peripheral nerve injury.
Animals ; Central Nervous System Sensitization ; Constriction ; Cytochromes ; Dehydroepiandrosterone ; Dehydroepiandrosterone Sulfate ; Hyperalgesia ; N-Methylaspartate ; Neuralgia ; Nitric Oxide Synthase Type II ; Nitric Oxide Synthase ; Nitric Oxide ; Oxidative Stress ; Peripheral Nerve Injuries ; Phosphorylation ; Rats ; RNA, Messenger ; Rodentia ; Sciatic Nerve ; Spinal Cord ; Spinal Cord Dorsal Horn

BACKGROUND: Postherpetic neuralgia (PHN) is a common and painful complication of acute herpes zoster. In some cases, it is refractory to medical treatment. Preventing its occurrence is an important issue. We hypothesized that applying nerve blocks during the acute phase of herpes zoster could reduce PHN incidence by attenuating central sensitization and minimizing nerve damage and the anti-inflammatory effects of local anesthetics and steroids. METHODS: This systematic review and meta-analysis evaluates the efficacy of using nerve blocks to prevent PHN. We searched the MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov and KoreaMed databases without language restrictions on April, 30 2014. We included all randomized controlled trials performed within 3 weeks after the onset of herpes zoster in order to compare nerve blocks vs active placebo and standard therapy. RESULTS: Nine trials were included in this systematic review and meta-analysis. Nerve blocks reduced the duration of herpes zoster-related pain and PHN incidence of at 3, 6, and 12 months after final intervention. Stellate ganglion block and single epidural injection did not achieve positive outcomes, but administering paravertebral blockage and continuous/repeated epidural blocks reduced PHN incidence at 3 months. None of the included trials reported clinically meaningful serious adverse events. CONCLUSIONS: Applying nerve blocks during the acute phase of the herpes zoster shortens the duration of zoster-related pain, and somatic blocks (including paravertebral and repeated/continuous epidural blocks) are recommended to prevent PHN. In future studies, consensus-based PHN definitions, clinical cutoff points that define successful treatment outcomes and standardized outcome-assessment tools will be needed.
Anesthetics, Local ; Central Nervous System Sensitization ; Herpes Zoster* ; Humans ; Incidence ; Injections, Epidural ; Nerve Block* ; Neuralgia, Postherpetic* ; Stellate Ganglion ; Steroids

Good pain control after surgery is important to facilitate overall recovery, improve patient satisfaction, decrease morbidity, and reduce health care cost. However, despite heightened awareness and development of new guidelines in recent decades, we have failed to make major improvements in postoperative pain control. Currently available analgesic therapies have limited efficacy, and pain after surgery continues to be a significant clinical problem. Our goal is to develop more effective and safer clinical strategies that will eliminate or greatly reduce postoperative pain, and a better understanding of the mechanisms of pain induced by surgery would be essential to achieve this goal. Evidence suggests that the pathophysiological mechanisms and optimal treatment of postoperative pain are different from many other painful conditions. Recognizing the necessity and importance of relevant pre-clinical models, we have developed and characterized rodent incision models that have close similarities to postoperative pain in patients. Previous studies have demonstrated the clinical relevance and translatability of these pre-clinical models of postoperative pain. In this review, we describe the rodent incision pain models, and summarized our current understanding of the mechanisms of postoperative pain, highlighting key findings from our previous studies using these models.
Central Nervous System Sensitization ; Health Care Costs ; Humans ; Pain, Postoperative* ; Patient Satisfaction ; Rodentia

BACKGROUND: A low dose of ketamine can be an effective preemptive analgesic by preventing central sensitization when administered before surgical trauma. In this study, we assessed the preemptive analgesic effect of low-dose ketamine administered intravenously to patients undergoing arthroscopic rotator cuff repair with intra articular ropivacaine injection. METHODS: This randomized, double-blinded study included fifty-six patients scheduled for elective arthroscopic rotator cuff repair. Normal saline (group C) or 0.5 mg/kg of ketamine (group K) was injected intravenously before the skin incision. An intra articular injection using 20 ml of 0.75% ropivacaine was performed in both groups just before wound closure by the surgeon at the end of the surgery. Postoperative pain was assessed by the numeric rating scale (NRS) in the post-anesthesia care unit (PACU) and at 12, 24, and 48 hours postoperatively. The total dose of fentanyl consumption and side effects were recorded. RESULTS: There were no significant differences between the C and K groups for the NRS of pain in the PACU and at 12, 24, and 48 hours after the surgery. In addition, there was also no significant difference in total fentanyl consumption between the two groups. CONCLUSIONS: Preemptive ketamine did not reduce preemptive pain scores and fentanyl consumption in patients who underwent arthroscopic rotator cuff repair with intra articular local anesthetic injection. Therefore, more aggressive and multimodal pain control is required in patients undergoing arthroscopic shoulder surgery regardless of the use of preemptive intravenous ketamine injection.
Central Nervous System Sensitization ; Fentanyl ; Humans ; Ketamine* ; Pain, Postoperative* ; Rotator Cuff* ; Shoulder ; Skin ; Wounds and Injuries

Chronic refractory cough is defined as a cough that persists despite guideline based treatment. It is seen in 20-46% of patients presenting to specialist cough clinics and it has a substantial impact on quality of life and healthcare utilization. Several terms have been used to describe this condition, including the recently introduced term cough hypersensitivity syndrome. Key symptoms include a dry irritated cough localized around the laryngeal region. Symptoms are not restricted to cough and can include globus, dyspnea, and dysphonia. Chronic refractory cough has factors in common with laryngeal hypersensitivity syndromes and chronic pain syndromes, and these similarities help to shed light on the pathophysiology of the condition. Its pathophysiology includes cough reflex sensitivity, central sensitization, peripheral sensitization, and paradoxical vocal fold movement. Chronic refractory cough often occurs after a viral infection. The diagnosis is made once the main disease that causes chronic cough have been excluded (or treated) and cough remains refractory to medical treatment. Treatments include speech pathology interventions using techniques adapted from the treatment of hyperfunctional voice disorders, as well as the use of centrally acting neuromodulators such as gabapentin and pregabalin. Potential new treatments in development also show promise.
Central Nervous System Sensitization ; Chronic Pain ; Cough* ; Delivery of Health Care ; Diagnosis ; Dysphonia ; Dyspnea ; Humans ; Hypersensitivity ; Neurotransmitter Agents ; Pregabalin ; Quality of Life ; Reflex ; Specialization ; Speech-Language Pathology ; Vocal Cords ; Voice Disorders

BACKGROUND: Opioid induced hyperalgesia (OIH) is related with high opioid dosage, a long duration of opioid administration, and abrupt discontinuation of infused opioids in anesthetic settings. Ketamine is known to attenuate OIH efficiently, but methods of administration and methods to quantify and assess a decrease in OIH vary. We demonstrated the existence of remifentanil-induced hyperalgesia and investigated the ability of ketamine to attenuate OIH. METHODS: Seventy-five patients undergoing laparoscopic gynecologic surgery under remifentanil-based anesthesia were assigned to one of the following groups: (1) group RL (remifentanil 0.05 microg/kg/min), (2) group RH (remifentanil 0.3 microg/kg/min), or (3) group KRH (remifentanil 0.3 microg/kg/min + ketamine 0.5 mg/kg bolus with 5 microg/kg/min infusion intraoperatively). Desflurane was administered for maintenance of anesthesia to target bispectral index scores (40-60) and hemodynamic parameters (heart rate and blood pressure < +/- 20% of baseline values). All parameters related to OIH and its attenuation induced by ketamine were investigated. RESULTS: There was no significant difference among the three groups related to demographic and anesthetic parameters except the end-tidal concentration of desflurane. Additional analgesic consumption, numerical rating scale scores at 6 and 24 h, and cumulative fentanyl dose were significantly higher in group RH than in the other two groups. The value difference of the Touch-Test sensory evaluation was significantly higher negative in group RH than in the other two groups. CONCLUSIONS: Remifentanil-induced hyperalgesia is significantly attenuated by intraoperative bolus and infusion of ketamine. Ketamine also decreased tactile sensitization, as measured by Touch-Test sensory evaluation.
Analgesics, Opioid ; Anesthesia ; Blood Pressure ; Central Nervous System Sensitization ; Female ; Fentanyl ; Gynecologic Surgical Procedures ; Hemodynamics ; Humans ; Hyperalgesia* ; Ketamine*

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has been a frustrating condition that is characterized by pain in areas including the perineum, rectum, prostate, penis, testicles, and abdomen. Unfortunately, effective treatment for the chronic pelvic pain remains uncertain and most urologists still believe we have little to offer these patients once traditional therapy including antibiotics has failed. Proposed mechanisms in development of pain in CP/CPPS is that biological insult in the context of alterations in psychoimmunoneurendocrine factors produces the chronic pain experience. There is increasing evidence that the chronic pain is associated with long-lasting changes both to the structure and function of the nervous system. Nerve injury, such as in neuropathic pain, peripheral sensitization, and central sensitization might play an important role in CP/CPPS and therefore be a therapeutic target. Newer medications, such as the anticonvulsant gabapentin and pregabalin, are becoming increasingly used for neuropathic pain in CP/CPPS. Now, urologists should understand the neuropathic pain in CP/CPPS and become on some level a pain doctor.
Abdomen ; Anti-Bacterial Agents ; Central Nervous System Sensitization ; Chronic Pain ; Humans ; Male ; Nervous System ; Neuralgia* ; Pelvic Pain* ; Penis ; Perineum ; Prostate ; Prostatitis ; Rectum ; Testis ; Pregabalin

It has been reported that long-term enhancement of superficial dorsal horn (DHs) excitatory synaptic transmission underlies central sensitization, secondary hyperalgesia, and persistent pain. We tested whether impaired clearance of K+ and glutamate by glia in DHs may contribute to initiation and maintenance of the CNS pain circuit and sensorimotor abnormalities. Transient exposure of the spinal cord slice to fluorocitrate (FC) is shown to be accompanied by a protracted decrease of the DHs optical response to repetitive electrical stimulation of the ipsilateral dorsal root, and by a similarly protracted increase in the postsynaptic response of the DHs like LTP. It also is shown that LTP(FC) does not occur in the presence of APV, and becomes progressively smaller as [K+]o in the perfusion solution decreased from 3.0 mM to 0.0 mM. Interestingly LTP(FC) is reduced by bath application of Bic. Whole-cell patch recordings were carried out to evaluate the effects of FC on the response of DHs neurons to puffer-applied GABA. The observations reveal that transient exposure to FC is reliably accompanied by a prolonged (>1 hr) depolarizing shift of the equilibrium potential for the DHs neuron transmembrane ionic currents evoked by GABA. Considered collectively, the findings demonstrate that LTP(FC) involves (1) elevation of [K+]o in the DHs, (2) NMDAR activation, and (3) conversion of the effect of GABA on DHs neurons from inhibition to excitation. It is proposed that a transient impairment of astrocyte energy production can trigger the cascade of dorsal horn mechanisms that underlies hyperalgesia and persistent pain.
Animals ; Astrocytes ; Baths ; Central Nervous System Sensitization ; Electric Stimulation ; gamma-Aminobutyric Acid* ; Glutamic Acid ; Horns ; Hyperalgesia ; Neuroglia ; Neurons ; Perfusion ; Posterior Horn Cells* ; Rats* ; Spinal Cord* ; Spinal Nerve Roots ; Synaptic Transmission

Ketamine has been shown to have analgesic effect by blocking N-methyl-D-aspartate receptor, thus preventing and reducing central sensitization caused by peripheral nociceptive stimulation. However, due to lack of knowledge about its safety and toxicity in the central nervous system, either epidural or intrathecal injection of ketamine still remains controversial. Here, we describe a case report of satisfactory pain relief after the addition of ketamine in epidural injection in a patient with severe herpes zoster pain that was refractory to conventional medication, intravenous opioids and continuous epidural block. This case indicates the viability of epidural ketamine injection in patients with intractable herpetic neuralgia.
Analgesia, Epidural ; Analgesics, Opioid ; Central Nervous System ; Central Nervous System Sensitization ; Herpes Zoster ; Humans ; Injections, Epidural ; Injections, Spinal ; Ketamine* ; N-Methylaspartate ; Neuralgia*