Takaya Inoue

Experimental Neuropathy in Mice Is Associated with Delayed Behavioral Changes Related to Anxiety and Depression

BACKGROUND:Patients with chronic pain frequently suffer affective disorders, particularly anxiety and depression. Although clinical research on the relationship between pain and depressive symptoms has been done, it is not clear whether pain causes depression or depression exaggerates pain. To investigate the relation between pain and affect, we measured anxiety and depression-related behaviors in mice after spinal nerve ligation using classical behavioral tests. METHODS:After unilateral ligation of the left fifth lumbar nerve, we measured pain behaviors using von Frey and radiant heat tests. Activity level, anxiety-related behaviors, and depression-related behaviors were tested with open field, light-dark exploration, elevated plus-maze, and forced swim tests. RESULTS:Sensory hypersensitivity was observed within a few days after ligation. Anxiety and depression-related behaviors were not seen 2 and 7 days after ligation. However, 15 and 30 days after ligation we found clear evidence of anxiety and depression-related behaviors, without loss of mobility. CONCLUSIONS:Nerve injury can trigger affective disturbances in mice that appear much later than sensory hypersensitivity.

NF-κB decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model

Pro-inflammatory cytokines have been shown to be involved in the genesis, persistence, and severity of neuropathic pain following nerve injury. The transcription factor, nuclear factor-kappa B (NF-κB), plays a pivotal role in regulating pro-inflammatory cytokine gene expression. To elucidate the role of NF-κB in the pathogenesis of neuropathic pain, using a gene-based approach of NF-κB decoy, we tested whether the activated NF-κB affected pain behavior via the expression of inflammatory mediators. Single endoneurial injections of NF-κB decoy, at the site of nerve lesion, significantly alleviated thermal hyperalgesia for up to 2 weeks and suppressed the expression of mRNA of the inflammatory cytokines, iNOS, and adhesion molecules at the site of nerve injury. This finding suggests that a perineural inflammatory cascade, that involves NF-κB, is involved in the pathogenesis of neuropathic pain.

Intrathecal administration of a new nitric oxide donor, NOC-18, produces acute thermal hyperalgesia in the rat.

A nitric oxide releasing compound, NOC-18, was injected intrathecally in order to determine the role of NO in spinal nociceptive mechanisms in rats. The nociceptive threshold was evaluated by the radiant heat tail-flick test. The effects of intrathecal injection of N-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor; methylene blue (MB), a soluble guanylate cyclase inhibitor and hemoglobin (Hb), an NO scavenger, on the nociceptive threshold were measured in the presence and absence of 0.1, 1 and 10 microg of NOC-18. The results were compared with a control group of rats which were injected with the same volume of normal saline. NOC-18 caused a dose-dependent curtailment of the tail-flick latency during the period from 15 to 150 min. L-NAME, MB and Hb all produced prolongation of the tail-flick latency during the same time period. The hyperalgesia induced by this concentration range of NOC-18 was completely blocked by Hb, but was not affected by either L-NAME or MB. These findings indicate that NO plays a direct role in thermal hyperalgesia in the spinal cord, and that an another pathway in addition to the NO-cGMP pathway may be involved.

Intrathecal lithium reduces neuropathic pain responses in a rat model of peripheral neuropathy.

Abstract We tested the ability of lithium (Li+) to block heat hyperalgesia, cold allodynia, mechanical allodynia and mechanical hyperalgesia in rats experimentally subjected to painful peripheral neuropathy. Chronic constrictive injury (CCI) to the sciatic nerve induced persistent hyperalgesia and allodynia. Intrathecal injection of Li+ (2.5–40 &mgr;mol) into the region of lumbar enlargement dose‐dependently reduced heat hyperalgesia, cold allodynia and mechanical allodynia for 2–6 h after injection, but had no effect on mechanical hyperalgesia. Li+ had no significant effect on responses from control and sham‐operated animals. Intrathecal injection of myo‐inositol (2.5 mg) significantly reversed both the anti‐hyperalgesic and anti‐allodynic effect of Li+. These findings suggest that intrathecal Li+ suppresses neuropathic pain response in CCI rats through the intracellular phosphatidylinositol (PI) second messenger system in spinal cord neurons. Lithium (Li+) has already found widespread clinical application; these results suggest that its therapeutic utility may be extended to include treatment of neuropathic pain syndromes resulting from peripheral nerve injury.

Continuous Femoral Versus Epidural Block for Attainment Of 120° Knee Flexion After Total Knee Arthroplasty: A Randomized Controlled Trial

We conducted the prospective randomized controlled trial to test that continuous femoral nerve block (CFNB) improves attainment of 120° knee flexion compared to continuous epidural analgesia (CEA). Sixty-six patients scheduled for unilateral total knee arthroplasty were randomized into two groups; infusion of ropivacaine 0.15% into CEA or CFNB to third postoperative days. We studied the time required to attain 120° knee flexion, variations in thigh and calf circumferences around the treated knee, pain scores, rehabilitation milestones, the need for adjuvant analgesics, and side effects. CFNB patients attained earlier knee flexion to 120°, lower variations in thigh and calf circumferences, less pain during rehabilitation, and less need for adjuvant analgesics. CFNB is a better pain management strategy that accelerates knee flexion rehabilitation.

The effects of propofol on NMDA- or nitric oxide-mediated neurotoxicity in vitro

Acute brain ischemia causes neurotoxic cascades including NMDA receptors and NO. Propofol, an i.v. anesthetic, is thought to have a neuroprotective effect. We investigated the influence of propofol on NMDA/NO neurotoxicity using Shibutas established model of primary brain cultures. Cortical neurons prepared from E16 were used after 13–14 days in culture. The neurons were exposed to various concentrations of propofol with NMDA or NO-donor. The survival rates of neurons exposed to 30 μM NMDA with or without 300 μM propofol were 12.1 ± 2.2% and 11.9 ± 2.2%, respectively. The survival rates exposed to 30 μM NO-donor with or without 300 μM propofol were 11.2 ± 4.2% and 14.0 ± 3.9%, respectively. These results suggest that neuroprotective effect of propofol is limited and propofol does not offer advantages over thiopental against NMDA/NO-induced cytotoxicity.

The influence of the timing of administration of thiopentone sodium on nitric oxide-mediated neurotoxicity in vitro

Thiopentone sodium is a highly useful pharmacological agent that provides a neuroprotection against cerebral ischaemia. Since not all patients can receive thiopentone sodium before cerebral ischaemia occurs, we investigated the influence of timing of thiopentone sodium administration on the neurotoxicity induced by nitric oxide (NO) using Shibutas established model of primary brain cultures. Cortical neurones prepared from 16-day gestational rat foetuses were used after 13-14 days in culture. The cells were exposed to an NO-donor, NOC-5 at 30 microM. Thiopentone sodium administered at 30 and 10 min before or 5, 10 and 15 min after exposure to NOC-5, but not thereafter, significantly attenuated NO-induced neurotoxicity compared with controls. The survival rate of the neurones in which thiopentone sodium was administered at 15 min after exposure to NOC-5 was 55.7+/-2.4%, compared to a 10.0+/-1.6% survival rate in neurones when thiopentone sodium was administered at 30 min after exposure to NOC-5. These findings demonstrate that thiopentone sodium, which protects cerebral cortical neurones against NO-mediated cytotoxicity, should be given as soon as possible in case ischaemic or hypoxic neuronal damage is predicted.

Long-lasting effect of transcutaneous electrical nerve stimulation on the thermal hyperalgesia in the rat model of peripheral neuropathy

We demonstrate here unexpectedly long-lasting effect of transcutaneous electrical nerve stimulation (TENS) to alleviate thermal hyperalgesia in rats with peripheral neuropathy produced by constriction of sciatic nerve. For TENS groups, electrical stimulation for 16.7 min (1 Hz, paired current, 12 mA, 5-ms interval, 0.2-ms duration, 999 pairs), once a day, was delivered for 5 consecutive days, under halothane anesthesia (Hal-TENS group) or pentobarbital anesthesia (Pent-TENS group). For non-TENS groups, only the anesthesia was delivered (Hal-no TENS group, Pent-no TENS group). For the control group, neither anesthetics nor TENS was delivered. To evaluate hyperalgesia, paw withdrawal latency (PWL) to radiant heat was measured before nerve constriction and five times after the constriction; just before TENS and at 1, 3, 7, and 14 days after the completion of TENS. Compared to the non-TENS groups, rats in the TENS groups showed significantly reduced thermal hyperalgesia at least for 3 days (Pent-TENS group) or for 7 days (Hal-TENS group) after TENS. These results indicate a possible long-lasting therapeutic effect of TENS applied under general anesthesia.

The effect of electroconvulsive treatment on thermal hyperalgesia and mechanical allodynia in a rat model of peripheral neuropathy.

We tested the ability of electroconvulsive treatment (ECT) to block thermal hyperalgesia and mechanical allodynia in rats with peripheral neuropathy.Repeated ECT (six times daily) significantly reduced thermal hyperalgesia 48 h after the end of the final treatment but had no significant effects on mechanical allodynia. Single ECT had no significant effect on thermal hyperalgesia or mechanical allodynia. Neither single nor repeated ECT had any significant effect on the withdrawal response of sham-operated paws and untreated rats to thermal and mechanical stimuli. The antithermal hyperalgesic effect of repeated ECT was reversed by the previous administration of nifedipine (L-type Ca2+ channel blocker). We conclude that, due to effects on the voltage dependent calcium channel, ECT modified one of the pain behaviors induced by nerve injury. ECT may be of use in the treatment of human neuropathic pain. Implications: We showed that repeated electroconvulsive treatment reduced pain responses to heat stimulation after sciatic nerve injury in rats. This study implies a possible therapeutic effect of electroconvulsive treatment on neuropathic pain. (Anesth Analg 1998;86:584-7)