Takashi Suto

Individual Differences in Acute Pain-induced Endogenous Analgesia Predict Time to Resolution of Postoperative Pain in the Rat

Background:Chronic postsurgical pain, a significant public health problem, occurs in 10 to 50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of chronic postsurgical pain. The relation between CPM and recovery from surgery has not been examined in preclinical models. Methods:CPM was assessed in individual rats and correlated with each animal’s time course of recovery of hypersensitivity after partial spinal nerve ligation. The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine &bgr;-hydroxylase–conjugated saporin to ablate these pathways. Behavioral hypersensitivity, static weight bearing, and spinal glial activation were measured after partial spinal nerve ligation. Results:The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001; r = 0.660). CPM induced the release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or dopamine &bgr;-hydroxylase-saporin. Dopamine &bgr;-hydroxylase-saporin also slowed recovery and enhanced spinal glial activation after partial spinal nerve ligation surgery. Ongoing activation of these pathways was critical to sustained recovery because intrathecal dopamine &bgr;-hydroxylase-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery. Conclusion:Collectively, these studies provide a clear back-translation from clinical observations of CPM and chronic postsurgical pain and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

Supraspinal actions of nociceptin/orphanin FQ, morphine and substance P in regulating pain and itch in non‐human primates

Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor agonists display a promising analgesic profile in preclinical studies. However, supraspinal N/OFQ produced hyperalgesia in rodents and such effects have not been addressed in primates. Thus, the aim of this study was to investigate the effects of centrally administered ligands on regulating pain and itch in non‐human primates. In particular, nociceptive thresholds affected by intracisternal N/OFQ were compared with those of morphine and substance P, known to provide analgesia and mediate hyperalgesia, respectively, in humans.

Long-term Effect of Sciatic Nerve Block with Slow-release Lidocaine in a Rat Model of Postoperative Pain

Background:Postoperative pain management is important for preventing perioperative complications. The authors examined the effectiveness of controlled-release lidocaine for sciatic nerve block in a rat model of postoperative pain. Methods:The authors created a novel slow-release lidocaine sheet (SRLS) with polylactic-coglycolic acid. In male Sprague-Dawley rats (postoperative pain model), the authors applied the SRLS, lidocaine alone, or polylactic-coglycolic acid (control) near the ipsilateral sciatic nerve just before making the paw incision. Mechanical hypersensitivity was assessed using von Frey filaments, and c-fos expression was examined in the spinal cord dorsal horn at segments L4–L5. Neurotoxicity and muscle toxicity were also evaluated via histopathology. Results:The SRLS (30%, w/w) continuously released lidocaine for 1 week in vitro. The withdrawal threshold in the SRLS-treated group was higher than that in the control group at all time points measured (2 h to 7 days). The withdrawal threshold in the lidocaine-treated group was higher than that in the control group only at 2 h after paw incision. The mean number of c-fos immunoreactive neurons in the SRLS-treated group was lower than in the control group at 2, 5, and 48 h after paw incision and lower than in the lidocaine-treated group at 5 and 48 h after paw incision. On histopathology, signs of inflammation were only slightly present in the muscle and nerve tissues of the SRLS-treated group. Conclusions:Single treatment with the SRLS inhibited hyperalgesia and c-fos expression in the spinal cord dorsal horn for 1 week. Slow-release local anesthetics are promising for the management of postoperative pain.

Impaired Pain-evoked Analgesia after Nerve Injury in Rats Reflects Altered Glutamate Regulation in the Locus Coeruleus.

Background:Patients with neuropathic pain show reduced endogenous analgesia induced by a conditioned noxious stimulus. Here, the authors tested whether peripheral nerve injury impairs descending noradrenergic inhibition from the locus coeruleus (LC) after L5–L6 spinal nerve ligation (SNL) in rats. Methods:A subdermal injection of capsaicin was used to examine noxious stimulation–induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity in normal and SNL rats. The authors also examined the role of presynaptic metabotropic glutamate receptors or the astroglial glutamate transporter-1 (GLT-1). Results:SNL increased basal extracellular glutamate concentration in the LC (170.1%; 95% CI, 44.7 to 295.5; n = 15) and basal spinal cord noradrenaline release (252.1%; 95% CI, 113.6 to 391.3; n = 15), which was associated with an increased tonic LC neuronal activity and a down-regulation of GLT-1 in the LC. SNL reduced NSIA (−77.6%; 95% CI, −116.4 to −38.8; n = 14) and capsaicin evoked release of glutamate in the LC (−36.2%; 95% CI, −49.3 to −23.2; n = 8) and noradrenaline in the spinal cord (−38.8%; 95% CI, −45.1 to −32.5; n = 8). Capsaicin-evoked LC neuronal activation was masked in SNL rats. Removing autoinhibition of glutamatergic terminals by metabotropic glutamate receptor blockade or increasing GLT-1 expression by histone deacetylase inhibition restored NSIA in SNL rats. SNL-induced impairment of NSIA was mimicked in normal rats by knockdown of GLT-1 in the LC. Conclusions:These results suggest that increased extracellular glutamate in the LC consequent to down-regulation of GLT-1 contributes to LC dysfunction and impaired pain-evoked endogenous analgesia after nerve injury.

Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain.

&NA; Peripheral nerve injury and gabapentin increase noradrenergic tone in the prefrontal cortex and cause impairment of attentional behavior via &agr;1‐adrenoceptor mediated mechanisms. &NA; Chronic pain after peripheral nerve damage is often accompanied by a reduction in prefrontal cortex (PFC)–related cognitive functions, which are regulated by noradrenaline, released from efferents originating in the locus coeruleus (LC). L5 to L6 spinal nerve ligation (SNL) in rats increased tissue content and extracellular concentrations of noradrenaline in microdialysates from the PFC, and impaired attentional level in the novel object recognition test. Systemic gabapentin, commonly used to treat chronic pain, impaired the novel object recognition task in normal but not SNL animals. Accordingly, gabapentin increased c‐fos expression in LC neurons and noradrenaline release in the PFC in normal animals, but in SNL animals, gabapentin failed to increase c‐fos expression in LC neurons projecting to the PFC and failed to increase noradrenaline release in the PFC. In contrast, locally perfused gabapentin reduced noradrenaline release in the PFC in vivo and in PFC synaptosomes in vitro. SNL‐ and gabapentin‐induced impairment of novel object recognition task were reversed by intraperitoneal injection of the &agr;1‐adrenoceptor antagonist prazosin. These results suggest that increase in noradrenergic tone, induced by nerve injury or gabapentin, impairs PFC functions possibly via &agr;1‐adrenoceptor–mediated mechanisms; that the net effect of gabapentin on noradrenaline release in the PFC would depend on sometimes opposing actions at different sites; and that nerve injury selectively impairs the response to gabapentin in PFC‐projecting neurons in the LC.

Effects of cardiopulmonary resuscitation at high altitudes on the physical condition of untrained and unacclimatized rescuers.

OBJECTIVE The authors experienced a case of prolonged cardiopulmonary resuscitation (CPR) on Mount Fuji (3776 m) that demanded strenuous work by the rescuers. The objective of this study was to provide information regarding the physiologic effects on the rescuers of performing CPR at moderate altitude. METHODS The effects of CPR at 2700 m and 3700 m above sea level on the physical condition of the rescuers were studied in 8 male volunteers. RESULTS Cardiopulmonary resuscitation for 5 minutes at 3700 m significantly reduced arterial blood oxygen saturation and increased rate-pressure products (P < .05). Scores on the Borg scale, a subjective score of fatigue, after CPR action at 2700 m (P < .05) and 3700 m (P < .01) were higher than the scores at sea level. CONCLUSIONS Prolonged CPR at high altitude exerts a significant physical effect upon the condition of rescuers. A role for mechanical devices should be considered wherever possible.

Long-term effect of epidural injection with sustained-release lidocaine particles in a rat model of postoperative pain

BACKGROUND Single applications of sustained-release local anaesthetics may provide prolonged pain relief without requiring indwelling catheters, but have not yet been investigated for epidural postoperative pain management. We synthesized injectable sustained-release lidocaine particles (SRLPs) from biodegradable polymers and examined their effect in a rat model of postoperative pain. METHODS Two types of polylactic acid particles, SRLP-10 and SRLP-25, containing 10% or 25% lidocaine, respectively, were generated and the lidocaine release was evaluated in vitro for 14 days. The SRLPs were then injected epidurally in the male Sprague-Dawley rats immediately before they received a hindpaw incision (the postoperative pain model), and hindpaw hypersensitivity was evaluated with the von Frey test. Motor paralysis and coordination were also assessed using a paralysis score and rota-rod test. Neurotoxicity and inflammation of the spinal cord, cauda equina, and tissue surrounding the injection site were histologically evaluated. RESULTS In vitro, SRLP-10 and SRLP-25 released lidocaine over 7 and 3 days, respectively. The in vivo injection of SRLP-10 (80 mg) produced anti-hypersensitivity with no evidence of motor paralysis for 7 days after the paw incision, and SRLP-25 (60 mg) inhibited postoperative hypersensitivity for 7 days. Temporary motor paralysis (15 min) was observed after the injection of SRLP-25 (even with 40 mg). Foreign body reactions were observed around the SRLP injection site at 1 and 4 weeks after injection. No histopathological changes were observed at 1 or 4 weeks. CONCLUSIONS The epidural injection of SRLPs produced prolonged anti-hypersensitivity in a rat model of postoperative pain with no major complications.

Effects of spinal anesthesia on the peripheral and deep core temperature in elderly diabetic patients undergoing urological surgery

PurposeThe effects of spinal anesthesia on temperature homeostasis have been well studied, but whether body temperature during spinal anesthesia exhibits the same characteristic changes in patients with diabetes mellitus (DM) has not been clarified. The present study measured body temperatures at the forehead and at the lower limb using a monitor of deep body temperature and compared patients with DM (n = 8) and without DM (n = 10).MethodsSubjects comprised 18 male patients (ASA physical status I or II) undergoing spinal anesthesia for urological surgery. Changes in deep body temperatures were measured using a Coretemp “deep-tissue” thermometer.ResultsAlthough the forehead temperature decreased slightly in both groups after spinal anesthesia, no significant differences were noted between groups. Conversely, although the foot temperature was elevated in both groups, temperature increases were smaller in DM patients (4.0° ± 0.3°C) than in controls (4.9° ± 0.6°C). Moreover, longer times were required to display increases of 1°C and 2°C for patients with DM (1°C: 19.1 ± 4.0 min; 2°C: 25.1 ± 4.2 min) compared with controls (1°C: 9.6 ± 1.3 min; 2°C: 13.1 ± 1.5 min).ConclusionThese data suggest that body temperature changes in patients with DM during spinal anesthesia are different from those of control patients, probably due to disorders of the vascular response.

Amitriptyline, but Not Pregabalin, Reverses the Attenuation of Noxious Stimulus-Induced Analgesia After Nerve Injury in Rats.

BACKGROUND:Noxious stimulus–induced analgesia (NSIA) is a type of conditioned pain modulation in rats that has been used to assess endogenous pain control systems. The descending noradrenergic system is involved in NSIA, and nerve injury induces plastic changes of descending noradrenergic neurons. Thus, we hypothesized that nerve injury would affect NSIA strength and that amitriptyline and pregabalin, which often are used for treating neuropathic pain, might further modulate NSIA through effects on the descending noradrenergic system. METHODS:We examined the change in NSIA over time after right L5 spinal nerve ligation (SNL) in rats by measuring the contralateral hind paw withdrawal threshold after left forepaw capsaicin injection. In addition, we examined NSIA after 5 daily intraperitoneal injection of amitriptyline or pregabalin. Microdialysis studies were performed to measure noradrenaline levels after left forepaw capsaicin injection in the left spinal dorsal horn in noninjured rats, SNL rats, and SNL rats that had received 5 daily intraperitoneal injections of amitriptyline or pregabalin. RESULTS:NSIA was dramatically attenuated 5 and 6 weeks after SNL (P < 0.001). The noradrenaline level in the lumbar spinal cord was significantly increased in noninjured rats receiving forepaw injection of capsaicin compared with vehicle injection (P < 0.001), but not in rats 6 weeks after SNL surgery. Five daily intraperitoneal injections of amitriptyline (10 mg/kg/d) or pregabalin (10 mg/kg/d) at 5 weeks after SNL gradually increased the ipsilateral hindpaw withdrawal threshold (P < 0.001). At 6 weeks after SNL, amitriptyline, but not pregabalin, reversed the attenuation of NSIA by SNL (P < 0.001) and increased the spinal noradrenaline level after forepaw injection of capsaicin (P = 0.005). CONCLUSIONS:These data suggest that endogenous analgesia in neuropathic pain states is strongly decreased from a certain time after nerve injury and that amitriptyline reverses the attenuation of endogenous analgesia through effects on the descending noradrenergic system.

Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System.

BACKGROUND The tricyclic antidepressant amitriptyline, the serotonin and noradrenaline reuptake inhibitor duloxetine, and gabapentinoids are first-line drugs for treatment of neuropathic pain. The analgesic effect of these drugs relates to brainstem-spinal descending noradrenergic systems. However, amitriptyline utilizes a variety of mechanisms for analgesia in neuropathic pain, and it is unclear which mechanism is most important. In the present study, we investigated the role of descending noradrenergic systems in the analgesic effect of these drugs for treatment of neuropathic pain. We also examined whether amitriptyline modifies the descending noradrenergic systems. METHODS Seven days after L5 spinal nerve ligation (SNL), rats received N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg) to degenerate noradrenergic fibers. The rats then received 5 daily intraperitoneal injections of amitriptyline (10 mg/kg), duloxetine (10 mg/kg), pregabalin (10 mg/kg), or gabapentin (50 mg/kg) from 21 days after SNL surgery. Paw withdrawal thresholds were determined to assess the effect of the drugs on hyperalgesia after SNL. To determine whether 5 daily injections of amitriptyline activated noradrenergic neurons in the locus coeruleus (LC) and spinal cord with or without DSP-4 treatment, we performed immunohistochemistry using antibodies for c-Fos and dopamine beta-hydroxylase (DβH). RESULTS Five daily injections of amitriptyline, duloxetine, pregabalin, and gabapentin exerted antihyperalgesic effects in SNL rats (P < .001; estimated treatment effect of amitriptyline [99% confidence interval]: 59.9 [35.1-84.7] g). The antihyperalgesic effects of duloxetine, pregabalin, and gabapentin were reversed by pretreatment with DSP-4 (P < .001, respectively). However, antihyperalgesia was still observed after treatment of amitriptyline in SNL rats with DSP-4 pretreatment (P < .001, 59.7 [30.0-89.3] g), and this analgesic effect was not reversed by the α2-adrenoceptor antagonist idazoxan (30 μg). Additionally, 5 daily injections of amitriptyline increased the ratio of c-Fos-immunoreactive (IR) cells in noradrenergic LC neurons in SNL rats with or without DSP-4 pretreatment (P < .001, respectively). Five daily injections of amitriptyline increased DβH-IR in the LC and the spinal dorsal horn of SNL rats (P < .001, respectively). With DSP-4 pretreatment, DβH-IR was dramatically decreased with or without 5 daily injections of amitriptyline (P < .001). CONCLUSIONS Five daily injections of amitriptyline produced antihyperalgesic effects against neuropathic pain despite suppression of noradrenergic descending inhibitory systems. Amitriptyline activated LC neurons and increased noradrenergic fibers density in SNL rats. These results suggest that amitriptyline could still produce analgesia under pathological dysfunction of the descending noradrenergic system. Amitriptyline may enhance the analgesic effect of drugs for neuropathic pain that require normal descending noradrenergic inhibition to produce analgesia, such as serotonin and noradrenaline reuptake inhibitors and gabapentinoids.BACKGROUND: The tricyclic antidepressant amitriptyline, the serotonin and noradrenaline reuptake inhibitor duloxetine, and gabapentinoids are first-line drugs for treatment of neuropathic pain. The analgesic effect of these drugs relates to brainstem-spinal descending noradrenergic systems. However, amitriptyline utilizes a variety of mechanisms for analgesia in neuropathic pain, and it is unclear which mechanism is most important. In the present study, we investigated the role of descending noradrenergic systems in the analgesic effect of these drugs for treatment of neuropathic pain. We also examined whether amitriptyline modifies the descending noradrenergic systems. METHODS: Seven days after L5 spinal nerve ligation (SNL), rats received N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg) to degenerate noradrenergic fibers. The rats then received 5 daily intraperitoneal injections of amitriptyline (10 mg/kg), duloxetine (10 mg/kg), pregabalin (10 mg/kg), or gabapentin (50 mg/kg) from 21 days after SNL surgery. Paw withdrawal thresholds were determined to assess the effect of the drugs on hyperalgesia after SNL. To determine whether 5 daily injections of amitriptyline activated noradrenergic neurons in the locus coeruleus (LC) and spinal cord with or without DSP-4 treatment, we performed immunohistochemistry using antibodies for c-Fos and dopamine beta-hydroxylase (D&bgr;H). RESULTS: Five daily injections of amitriptyline, duloxetine, pregabalin, and gabapentin exerted antihyperalgesic effects in SNL rats (P < .001; estimated treatment effect of amitriptyline [99% confidence interval]: 59.9 [35.1–84.7] g). The antihyperalgesic effects of duloxetine, pregabalin, and gabapentin were reversed by pretreatment with DSP-4 (P < .001, respectively). However, antihyperalgesia was still observed after treatment of amitriptyline in SNL rats with DSP-4 pretreatment (P < .001, 59.7 [30.0–89.3] g), and this analgesic effect was not reversed by the &agr;2-adrenoceptor antagonist idazoxan (30 &mgr;g). Additionally, 5 daily injections of amitriptyline increased the ratio of c-Fos-immunoreactive (IR) cells in noradrenergic LC neurons in SNL rats with or without DSP-4 pretreatment (P < .001, respectively). Five daily injections of amitriptyline increased D&bgr;H-IR in the LC and the spinal dorsal horn of SNL rats (P < .001, respectively). With DSP-4 pretreatment, D&bgr;H-IR was dramatically decreased with or without 5 daily injections of amitriptyline (P < .001). CONCLUSIONS: Five daily injections of amitriptyline produced antihyperalgesic effects against neuropathic pain despite suppression of noradrenergic descending inhibitory systems. Amitriptyline activated LC neurons and increased noradrenergic fibers density in SNL rats. These results suggest that amitriptyline could still produce analgesia under pathological dysfunction of the descending noradrenergic system. Amitriptyline may enhance the analgesic effect of drugs for neuropathic pain that require normal descending noradrenergic inhibition to produce analgesia, such as serotonin and noradrenaline reuptake inhibitors and gabapentinoids.