The antinociceptive effect of the asthma drug ibudilast in rat models of peripheral and central neuropathic pain

Ibudilast, an asthma drug, has demonstrated antinociceptive effects in several rat models of peripheral neuropathic pain, and a proposed mechanism of action is the inhibition of release of the cytokine tumor necrosis factor-α (TNF-α) from activated spinal microglia. Spinal glial activation has also been demonstrated in rat models of central neuropathic pain following spinal cord injury (SCI). The current study evaluated the effect of a short course of treatment with ibudilast on SCI-induced pain, and for comparison, following a chronic constriction injury (CCI; the Bennett model) of the sciatic nerve in rats. The effects of ibudilast treatment on spinal (SCI and CCI rats), and nerve tissue (CCI only) TNF-α content were also evaluated. Following an acute midthoracic SCI with a microvascular clip (20-g force), hindpaw withdrawal thresholds were significantly decreased, indicating below-level cutaneous tactile hypersensitivity. Likewise, unilateral loose ligation of the sciatic nerve led to a robust ipsilateral tactile hypersensitivity. Rats were treated with either ibudilast (10 mg/kg IP) or vehicle (2 mL/kg) during the period of robust and steady hindpaw hypersensitivity for each model--CCI rats were treated 14-16 days post-surgery, and SCI rats were treated 30-32 days post-surgery--and tested daily. Ibudilast ameliorated hindpaw hypersensitivity in both SCI and CCI rats, whereas vehicle treatment had no effect. Interestingly, repeated treatment led to increased baseline thresholds, beyond the duration of the drug half-life, suggesting persistent changes in neuropathic pain processing. In SCI rats, an increase in TNF-α content in spinal tissue rostral to the SCI was observed. Ibudilast treatment did not significantly alter this increase. In rats with a CCI, TNF-α content was markedly increased in the ipsilateral sciatic nerve and was partially reduced following ibudilast, but not vehicle, treatment. Ibudilast could be useful for the treatment of neuropathic pain of central as well as peripheral origin.     

Successful reduction of neuropathic pain associated with spinal cord injury via of a combination of intrathecal hydromorphone and ziconotide: a case report

STUDY DESIGN: Case report. OBJECTIVES: To report a novel management strategy for neuropathic pain management after spinal cord injury. SETTING: Outpatient spinal cord injury (SCI) clinic. METHODS: The patient demonstrated two neuropathic pain syndromes, namely at- and below-level pain. These syndromes were recalcitrant to conservative measures and a decision was made to proceed with intrathecal therapies. RESULTS: The patient's at-level pain was responsive to intrathecal hydromorphone but the below-level pain was unaffected by this intervention. Intrathecal ziconotide provided an opposite response with a positive effect observed on the below-level pain and minimal effect on the at-level pain. The combination of intrathecal ziconotide and hydromorphone provided effective relief for both components of the patient's SCI associated neuropathic pain. CONCLUSIONS: The combination of intrathecal ziconotide and hydromorphone has the potential to provide significant pain relief for patients with neuropathic pain associated with spinal cord injury.     

Acupuncture as a promising treatment for below-level central neuropathic pain: a retrospective study

BACKGROUND/OBJECTIVE: Below-level central neuropathic pain, a diffuse pain characterized by generalized burning, is commonly experienced by individuals with spinal cord injury (SCI). The objective of this study was to investigate the effects of an electroacupuncture protocol for the treatment of below-level central neuropathic pain developed at the Toronto Rehabilitation Institute, Lyndhurst Center, Toronto, Ontario, Canada. METHOD: Retrospective chart review. RESULTS: Thirty-six individuals with traumatic and nontraumatic SCI met the inclusion criteria. Of these, 24 showed improvement after treatment with the electroacupuncture protocol. Type of injury, level of injury, and duration of below-level central neuropathic pain was not correlated with improvement. However, individuals whose pain was described as bilateral (vs unilateral; P = 0.014) or symmetric (vs nonsymmetric; P = 0.026) were more likely to improve after acupuncture treatment. Overall, patients whose burning pain was bilateral, symmetric, and constant (P = 0.005) were the most likely to improve. CONCLUSION: This retrospective study suggests that the Lyndhurst Center Central Neuropathic Pain Acupuncture Protocol may be an effective treatment option for patients with SCI who are experiencing below-level central neuropathic pain. Additional prospective clinical studies are needed to confirm these findings.     

Neuropathic pain after traumatic spinal cord injury--relations to gender, spinal level, completeness, and age at the time of injury

STUDY DESIGN: Retrospective register study. OBJECTIVE: To investigate the predictive value of age at the time of injury, gender, level of injury, and completeness of injury for the development of at level and below level neuropathic pain. SETTING: "Spinalis", a postacute spinal cord injury (SCI) outpatient clinic, serving the greater Stockholm area (Sweden). METHOD: All patients who visited the clinic in 1995-2000 (402 patients) for the first time were examined. The following items were selected: at-level and below-level neuropathic pain according to the International Association for the Study of Pain (IASP) criteria, age at the time of injury, gender, level of injury according to ASIA, and completeness of injury. Mean time of 6 years after the injury. Results were analysed with chi(2) analysis and logistic regression. RESULTS: Of all patients examined, 13% had at level pain and 27% had below level pain. Neuropathic pain was less than half as frequent (26%) in the group aged less than 20 years at the time of injury as in the oldest group (58%). The increasing trend was mainly due to below-level pain up to 39 years of age, and due to at-level pain at ages 40 and above at the time of injury. No correlation was observed to gender, level of injury or completeness of injury, except for below level pain, which was associated with complete injury. CONCLUSION: The results show that neuropathic pain after SCI is common and occurs much more often in patients injured at higher ages. This indicates the importance of neuroanalgetic intervention, in particular for patients injured in higher ages.     

Riluzole treatment reduces motoneuron death induced by axotomy in newborn rats

Nerve injury in neonatal rats leads to considerable motoneuron death. We investigated whether treatment with riluzole (a presynaptic inhibitor of glutamate release) is able to enhance survival of motor units (MUs) in the slow soleus (Sol) and fast extensor digitorum longus (EDL) muscles after sciatic nerve crush in newborn rats. Examination of 3- to 4-month-old rats revealed a beneficial effect of riluzole treatment after injury carried out on the first day after birth. At this time increased MU survival occurred in both the Sol and EDL muscles. In rats with nerve injury carried out on the second day after birth, increased MU survival occurred only in the Sol. We conclude that although riluzole treatment can rescue motoneurons destined to die and improve muscle performance, its beneficial effect is age-dependent, and the difference between the rescue of Sol and EDL MUs may be due to the slower maturation of motoneurons to soleus muscle. These findings have important implications regarding the motoneuron properties required for riluzole's beneficial effect.     

Role of Rho-associated coiled-coil containing protein kinase in the spinal cord injury induced neuropathic pain

BACKGROUND CONTEXTSpinal cord injury (SCI) can lead to increased phosphorylation of p38 in spinal cord microglia. This is one of the main causes for the development of persistent pain. Recently, we reported our study on the activation of p38 mitogen-activated protein kinases (MAPK) in spinal microglia, which has been considered the key molecule for the onset and maintenance of neuropathic pain after peripheral nerve injury, using a rat model. We also reported that the RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) pathway mediates p38 activation in spinal microglia in peripheral nerve injury. But the precise mechanisms of neuropathic pain induced by SCI are still unclear.PURPOSEThis study aimed to examine the activation of microglia and the p38 MAPK expression in the lumbar spinal cord after thoracic SCI in rats, and the correlation to the therapeutic effect of ROCK inhibitor ripasudil in rats with SCI.STUDY DESIGNMale Sprague–Dawley rats underwent thoracic (T10) spinal cord contusion injury using an Infinite Horizon impactor device. SCI rats received ROCK inhibitor ripasudil (24 nmol/day or 240 nmol/day) from just before SCI to 3 days after SCI.METHODSThe mechanical threshold in the rat's hind paws was measured over four weeks. Morphology of microglia and phosphorylation of p38 (p-p38) in the lumbar spinal cord and were analyzed using immunohistochemistry.RESULTSThe p-p38 positive cell and Iba1 (a maker of microglia) positive area were significantly increased at the lumbar spinal dorsal horn (L4–5) 3 days and 7 days after SCI compared with the sham-control (p<.05), whereas phosphorylated p38 was co-localized with microglia. Three days after SCI, the intensity of phosphorylated p38 and Iba1 immunoreactive cells in the dorsal horn was significantly lower in the ripasudil treated groups than in the saline group. However, administration of ROCK inhibitor did not affect the numbers of microglia. Moreover, the withdrawal threshold of the ripasudil-treated rats was significantly higher than that of the saline-injected rats on 14 days and 28 days after SCI.CONCLUSIONSOur results suggest that activation of ROCK in spinal cord microglia is likely to have an important role in the activation of p38 MAPK, which has been considered as a key molecule that switches on neuropathic pain after SCI. Inhibition of ROCK signaling may offer a means in developing a novel neuropathic pain treatment after SCI. It may help patients with neuropathic pain after SCI.CLINICAL SIGNIFICANCEThe findings in the present study regarding intracellular mechanisms suggest that modulation of ROCK signaling may be a focus for novel treatment for neuropathic pain after SCI.     

Sensory function after cavernous haemangioma: a case report of thermal hypersensitivity at and below an incomplete spinal cord injury

Study design:Case report of a 42-year-old woman with non-evoked pain diagnosed with a cavernous C7-Th6 spinal haemangioma.Objectives:To assess the effect of intramedullary haemorrhage (IH) on nociception and neuropathic pain (NP) at and below an incomplete spinal cord injury (SCI).Setting:Sensorimotor Function Group, Hospital Nacional de Parapléjicos de Toledo (HNPT).Methods:T2*-susceptibility weighted image (SWI) magnetic resonance imaging (MRI) of spinal haemosiderin and a complete pain history were performed 8 months following initial dysaesthesia complaint. Thermal pain thresholds were assessed with short 1?s stimuli, while evidence for central sensitization was obtained with psychophysical electronic Visual Analogue Scale rating of tonic 10?s 3?°C and 48?°C stimuli, applied at and below the IH. Control data were obtained from 10 healthy volunteers recruited from the HNPT.Results:Non-evoked pain was present within the Th6 dermatome and lower legs. T2*-SWI MRI imaging detected extensive haemosiderin-rich IH (C7-Th5/6 spinal level). Cold allodynia was detected below the IH (left L5 dermatome) with short thermal stimuli. Tonic thermal stimuli applied to the Th6, Th10 and C7 dermatomes revealed widespread heat and cold allodynia.Conclusion:NP was diagnosed following IH, corroborated by an increase in below-level cold pain threshold with at- and below-level cold and heat allodynia. Psychophysical evidence for at- and below-level SCI central sensitization was obtained with tonic thermal stimuli. Early detection of IH could lead to better management of specific NP symptoms, an appreciation of the role of haemorrhage as an aggravating SCI physical factor, and the identification of specific spinal pathophysiological pain mechanisms.     

Antinociceptive effect of intrathecal administration of taurine in rat models of neuropathic pain

Purpose

Taurine is the most abundant amino acid in many tissues. Although taurine has been shown to be antinociceptive, in this report, our focus is to elucidate the mechanism and action site on neuropathic pain. This study used behavioural assessments to determine whether taurine attenuates neuropathic pain in the spinal cord.

Methods

Chronic constriction injury (CCI) to the sciatic nerve and streptozotocin-induced diabetic neuropathy were introduced to male Sprague-Dawley rats. We then assessed the antinociceptive effect of spinal injections of taurine (100, 200, 400, or 800 μg) using electronic von Frey, paw pressure, and plantar tests. To explore the effect of taurine on motor function, a rotarod test was performed, and in order to determine which neurotransmitter pathway is involved in taurine’s action, we examined how several antagonists of spinal pain processing receptors altered the effect of taurine 400 μg in a paw pressure test.

Results

Taurine alleviated mechanical allodynia, mechanical hyperalgesia, and thermal hyperalgesia in CCI rats and suppressed mechanical allodynia and hyperalgesia in diabetic rats. Significant effects were observed at 200 μg in both models. On the other hand, taurine dose-dependently affected motor performance, and a significant effect was seen at 400 μg. The antinociceptive effects were reversed completely by pretreatment with an intrathecal injection of strychnine, a glycine receptor antagonist.

Conclusion

The present study demonstrated that intrathecal administration of taurine attenuates different models of neuropathic pain, and these effects seem to be mediated by the activation of glycinergic neurotransmission. These findings suggest that taurine may be a candidate remedy for neuropathic pain.     

Activation of spinal GABA receptors attenuates chronic central neuropathic pain after spinal cord injury

In this study, we investigated the role of the spinal GABAergic system in central neuropathic painlike outcomes following spinal cord injury (SCI) produced by a spinal hemitransection at T13 of the rat. After SCI, mechanical allodynia develops bilaterally in both hind paws of the rat, lasting longer than 40 days, as evidenced by an increase in paw withdrawal frequency in response to a weak von Frey filament. In naive rats, intrathecal (i.t.) administration in the lumbar spinal cord of GABAA and GABAB receptor antagonists, bicuculline (1-5 microg) and phaclofen (0.1-5 microg), respectively, causes a dose-dependent increase in the magnitude of mechanical allodynia. The SCI-induced mechanical allodynia in both hind-paws is attenuated by i.t. administration in the lumbar spinal cord of GABAA or GABAB receptor agonists, muscimol (1 microg) or baclofen (0.5 microg), respectively. In electrophysiological experiments, rats with SCI show a bilateral increase in hyperexcitability in response to natural stimuli in wide dynamic range (WDR) neurons in the lumbar spinal dorsal horn. The topical application of muscimol (1 microg) or baclofen (0.5 microg) onto the lumbar cord surface reduce the SCIinduced increased responsiveness of WDR neurons. Inhibitory effects of muscimol and baclofen on both the behavioral mechanical allodynia and the hyperexcitability in WDR neuron with SCI compared to controls, were antagonized by pre-treatment of bicuculline (10 microg) and phaclofen (5 microg), respectively. This study provides behavioral and electrophysiological evidence for the important role of the loss of spinal inhibitory tone, mediated by activation of both GABAA and GABAB receptors, in the development of central neuropathic pain following SCI.     

Riluzole and methylprednisolone combined treatment improves functional recovery in traumatic spinal cord injury

The potential use of riluzole (a glutamate release inhibitor) alone or in combination with methyl-prednisolone (MP) in treating acute spinal cored injury (SCI) was examined. Rats received a contusion injury to the spinal cord using the NYU impactor and were treated with vehicle, riluzole (8 mg/kg), MP(30 mg/kg), or riluzole + MP at 2 and 4 h following injury. Animals continued to receive riluzole treatment (8 mg/kg) for a period of 1 week. The animals were then tested weekly for functional recovery using the BBB open field locomotor score. At the end of testing (6 weeks after injury), each spinal cord was examined for the amount of remaining tissue at the injury site and a myelination index was used to quantify remaining axons in the ventromedial white matter. In this study, only the combination treatment was found to significantly improve behavioral recovery as assessed using the BBB open field locomotor scale. In addition, the combination treatment promoted tissue sparing at the lesion epicenter, but had no clear effect on the index of myelination. The results of this study clearly demonstrate the potential beneficial effects of a combination approach in the treatment of traumatic SCI.     

Intravenous Lidocaine Relieves Spinal Cord Injury Pain: A Randomized Controlled Trial

Background: Neuropathic pain in spinal cord injury is a common challenging therapeutic condition. The current study examines the analgesic effect of the sodium channel blocker lidocaine on neuropathic pain in patients with spinal cord injury and the predictive role of concomitant evoked pain on pain relief with lidocaine.

Methods: Twenty-four spinal cord injury patients with neuropathic pain at or below the level of injury were randomized and completed a double-blind crossover trial of 5 mg/kg lidocaine and placebo infused over 30 min. Twelve patients reported evoked pain, and 12 patients had no evoked pain. Spontaneous and evoked pains were assessed using a visual analog scale and quantitative sensory testing.

Results: Lidocaine significantly reduced spontaneous pain in all patients (P < 0.01) and in each of the two groups with (P < 0.01) and without (P = 0.048) evoked pain, with no difference in number of responders (pain reduction >= 33%) between the patients with (n = 6) and without (n = 5) evoked pain. Lidocaine significantly relieved both at-level and below-level neuropathic pain and decreased brush-evoked dysesthesia but not cold allodynia, pinprick hyperalgesia, or pain evoked by repetitive pinprick.     

Intravenous lidocaine relieves spinal cord injury pain: a randomized controlled trial

BACKGROUND: Neuropathic pain in spinal cord injury is a common challenging therapeutic condition. The current study examines the analgesic effect of the sodium channel blocker lidocaine on neuropathic pain in patients with spinal cord injury and the predictive role of concomitant evoked pain on pain relief with lidocaine. METHODS: Twenty-four spinal cord injury patients with neuropathic pain at or below the level of injury were randomized and completed a double-blind crossover trial of 5 mg/kg lidocaine and placebo infused over 30 min. Twelve patients reported evoked pain, and 12 patients had no evoked pain. Spontaneous and evoked pains were assessed using a visual analog scale and quantitative sensory testing. RESULTS: Lidocaine significantly reduced spontaneous pain in all patients (P < 0.01) and in each of the two groups with (P < 0.01) and without (P = 0.048) evoked pain, with no difference in number of responders (pain reduction > or = 33%) between the patients with (n = 6) and without (n = 5) evoked pain. Lidocaine significantly relieved both at-level and below-level neuropathic pain and decreased brush-evoked dysesthesia but not cold allodynia, pinprick hyperalgesia, or pain evoked by repetitive pinprick. CONCLUSIONS: Lidocaine reduced neuropathic pain at and below the level of injury irrespective of the presence or absence of evoked pain. Results are consistent with a central-acting effect of sodium channel blockers acting on neuronal hyperexcitability. Agents (such as anticonvulsants or antiarrhythmics) with sodium channel-blocking properties may be a treatment option for spinal cord injury pain.     

The spinal antinociceptive effect of nocistatin in neuropathic rats is blocked by D-serine

BACKGROUND: The neuropeptide nocistatin (NST) has been implicated in the modulation of nociceptive responses in the spinal cord. Depending on the dose, both pronociceptive and antinociceptive effects have repeatedly been reported. The pronociceptive effect is most likely attributable to inhibition of synaptic glycine and gamma-aminobutyric acid release and a subsequent reduction in the activation of inhibitory glycine and gamma-aminobutyric acid receptors, but the mechanisms of its antinociceptive action have hitherto remained elusive. It has recently been demonstrated that synaptically released glycine contributes to N-methyl-D-aspartate receptor activation. The authors therefore investigated whether a reduction in glycine release might also account for the antinociceptive action of NST in neuropathic rats. METHODS: The authors analyzed the effects of spinally applied NST in the chronic constriction injury model of neuropathic pain. NST was injected intrathecally from nanomolar to picomolar doses and its effects on thermal paw withdrawal latencies were monitored. Furthermore, we tested whether D-serine (100 microg per rat), a full agonist at the glycine binding site of the N-methyl-D-aspartate receptor, would interfere with the effects of NST. RESULTS: At high doses (10 nmol/rat), intrathecally injected NST was pronociceptive, whereas lower doses (1 pmol/rat) elicited antinociception. The antinociceptive, but not the pronociceptive, action was occluded by intrathecal pretreatment with D-serine. L-serine, which does not bind to N-methyl-D-aspartate receptors, affected neither the pronociceptive nor the antinociceptive effect. CONCLUSIONS: These results demonstrate that NST produces a biphasic dose-dependent effect on neuropathic pain. The spinal antinociception by NST is most likely attributable to inhibition of glycine-dependent N-methyl-D-aspartate receptor activation.     

Mechanistic insights into posttraumatic syringomyelia based on a novel in vivo animal model. Laboratory investigation

OBJECT: Although posttraumatic syringomyelia (PTS) develops in up to 30% of patients after spinal cord injury (SCI), the pathophysiology of this debilitating complication is incompletely understood. To provide greater insight into the mechanisms of this degenerative sequela of SCI, the authors developed and characterized a novel model of PTS. METHODS: The spinal cords of 64 female Wistar rats were injured by 35-g modified aneurysm clip compression at the level of T6-7. Kaolin (5 microl of 500 mg/ml solution) was then injected into the subarachnoid space rostral to the site of the injury to induce inflammatory arachnoiditis in 22 rats. Control groups received SCI alone (in 21 rats), kaolin injection alone (in 15 rats), or laminectomy and durotomy alone without injury (sham surgery in 6 rats). RESULTS: The combination of SCI and subarachnoid kaolin injection resulted in a significantly greater syrinx formation and perilesional myelomalacia than SCI alone; SCI and kaolin injection significantly attenuated locomotor recovery and exacerbated neuropathic pain (mechanical allodynia) compared with SCI alone. We observed that combined SCI and kaolin injection significantly increased the number of terminal deoxytransferase-mediated deoxyuridine triphosphate nick-end labeled-positive cells at 7 days after injury (p<0.05 compared with SCI alone) and resulted in a significantly greater extent of astrogliosis and macrophage/microglial-associated inflammation at the lesion (p<0.05). CONCLUSIONS: The combination of compressive/contusive SCI with induced arachnoiditis results in severe PTS and perilesional myelomalacia, which is associated with enhanced inflammation, astrogliosis, and apoptotic cell death. The development of delayed neurobehavioral deficits and neuropathic pain in this model accurately reflects the key pathological and clinical conditions of PTS in humans.     

Virtual reality for the treatment of neuropathic pain in people with spinal cord injuries: A scoping review

Context: Virtual and augmented imagery are emerging technologies with potential to reduce the severity and impact of neuropathic pain in people with spinal cord injury (SCI).Objective: We aimed to identify and discuss studies using virtual and augmented reality applications for the management of neuropathic pain in people with spinal cord injury.Methods (data sources, data extraction): A systematic literature search was conducted using PRISMA scoping review guidelines. Articles were searched in PubMed, Embase and Web of Science databases using search terms relating to SCI, virtual and augmented reality and neuropathic pain. With no strong evidence for visual imagery in the treatment of pain in SCI patients, we selected exploratory, feasibility and more rigorous methodologies such as randomized controlled trials and case-control studies. We only selected studies evaluating the effects of visual imagery on neuropathic pain at or below the spinal cord injury level.Results: Of 60 articles located, we included nine articles involving 207 participants. All studies were exploratory using head-mounted devices or 3D and 2D screens with virtual walking or limb movement imagery. Outcomes included pain sensitivity, motor function and body ownership. Eight of the nine studies reported significant reductions in neuropathic pain intensity. However, given small sample sizes in all studies, results may be unreliable.Conclusion: Although the number of studies and individual sample sizes are small, these initial findings are promising. Given the limited options available for the effective treatment of neuropathic SCI pain and early evidence of efficacy, they provide valuable incentive for further research.     

Electroencephalographic slowing and reduced reactivity in neuropathic pain following spinal cord injury

STUDY DESIGN: Brain wave activity in people with paraplegia, with and without neuropathic pain, was compared to brain wave activity in matched able-bodied controls. OBJECTIVES: To investigate whether spinal cord injury with neuropathic pain is associated with a slowing of brain wave activity. SETTING: Australia. METHODS: Electroencephalographic (EEG) data were collected in the eyes open (EO) and eyes closed (EC) states from 16 participants with paraplegia (eight with neuropathic pain and eight without pain) and matched able-bodied controls. Common EEG artefacts were removed using independent component analysis (ICA). Peak frequency in the theta-alpha band and EEG power in the delta, theta, alpha and beta frequency bands were compared between groups. RESULTS: The results show significant slowing of the EEG in people with neuropathic pain, consistent with the presence of thalamocortical dysrhythmia (TCD). Furthermore, people with neuropathic spinal cord injury (SCI) pain had significantly reduced EEG spectral reactivity in response to increased or decreased sensory input flowing into the thalamocortical network, as modulated by the eyes open and eyes closed states. CONCLUSION: The results provide further evidence for alterations in brain electric activity that may underlie the development of neuropathic pain following SCI.     

The Spinal Antinociceptive Effect of Nocistatin in Neuropathic Rats Is Blocked by D-Serine

Background: The neuropeptide nocistatin (NST) has been implicated in the modulation of nociceptive responses in the spinal cord. Depending on the dose, both pronociceptive and antinociceptive effects have repeatedly been reported. The pronociceptive effect is most likely attributable to inhibition of synaptic glycine and [gamma]-aminobutyric acid release and a subsequent reduction in the activation of inhibitory glycine and [gamma]-aminobutyric acid receptors, but the mechanisms of its antinociceptive action have hitherto remained elusive. It has recently been demonstrated that synaptically released glycine contributes to N-methyl-d-aspartate receptor activation. The authors therefore investigated whether a reduction in glycine release might also account for the antinociceptive action of NST in neuropathic rats.

Methods: The authors analyzed the effects of spinally applied NST in the chronic constriction injury model of neuropathic pain. NST was injected intrathecally from nanomolar to picomolar doses and its effects on thermal paw withdrawal latencies were monitored. Furthermore, we tested whether D-serine (100 [mu]g per rat), a full agonist at the glycine binding site of the N-methyl-d-aspartate receptor, would interfere with the effects of NST.

Results: At high doses (10 nmol/rat), intrathecally injected NST was pronociceptive, whereas lower doses (1 pmol/rat) elicited antinociception. The antinociceptive, but not the pronociceptive, action was occluded by intrathecal pretreatment with D-serine. L-serine, which does not bind to N-methyl-d-aspartate receptors, affected neither the pronociceptive nor the antinociceptive effect.     

Thermal and mechanical antinociceptive action of spinal vs peripherally administered clonidine in the rat inflamed knee joint model

It has been demonstrated recently that in addition to its spinal analgesic actions, the alpha 2 adrenoreceptor agonist clonidine also has peripheral analgesic activity. Few data are available regarding the antinociceptive effects of spinal vs peripherally delivered clonidine in inflammatory pain. Thus we have studied spinal (intrathecal = i.t.) and peripheral (intra-articular = i.a.) administration of clonidine in the rat inflamed knee joint model. Thermal and mechanical antinociception was assessed in rats over 28 h using a modified Hargreaves box and von Frey hairs after induction of tonic persistent inflammatory pain by injection of a kaolin-carrageenan mixture into the right knee joint. Thirty minutes after injection of kaolin-carrageenan, clonidine was administered via an i.t. catheter or by i.a. injection into the right inflamed knee joint or by subcutaneous injection (s.c.) (highest effective intra-articular dose). The specific site of action was assessed using the alpha 2 antagonist yohimbine i.t., i.a. or s.c. Clonidine i.t. resulted in thermal and mechanical antinociception during ongoing inflammation, which was not enhanced by inflammation. In contrast, i.a. delivery of clonidine, which also produced a dose- dependent thermal and mechanical antinociceptive effect, revealed a leftward shift in the antinociceptive activity produced by ongoing inflammation. Yohimbine inhibited the antinociceptive action of clonidine at the site of delivery. We suggest that clonidine produces potent thermal and mechanical antinociception regardless of the route of administration. However, chronic inflammatory processing appears to enhance the antinociceptive efficacy of the peripheral alpha 2 agonist.      

Intrathecal adenosine interacts with a spinal noradrenergic system to produce antinociception in nerve-injured rats.

BACKGROUND: Adenosine analogs produce antinociception in animal models of acute pain, reduce hypersensitivity in models of inflammatory and nerve-injury pain, and stimulate neurotransmitter release in the brain. Adenosine itself is entering clinical trials for analgesia, and the current study examined the effect, mechanisms of action, and interaction with noradrenergic systems of intrathecal adenosine in a rat model of neuropathic pain. METHODS: The left L5 and L6 spinal nerve roots were ligated and, 1 week later, an intrathecal catheter was inserted in male rats. Withdrawal threshold to mechanical stimulation of the left hind paw was determined before and after surgery, confirming mechanical hypersensitivity. The effects of intrathecal adenosine, clonidine, and their combination on withdrawal threshold were determined, and reversal of the effects of adenosine by adenosine and alpha2-adrenergic antagonists and by destruction of noradrenergic nerve terminals was tested. Finally, spinal cord slices were perfused in vitro with the adenosine agonist 5'-N-ethylcarboxamide adenosine, and norepinephrine release was measured. RESULTS: Intrathecal adenosine and clonidine reduced hypersensitivity and interacted in an additive manner. The effects of adenosine were blocked by intrathecal injection of A1 but not A2 adenosine receptor antagonists, by an alpha2-adrenergic antagonist, and by destruction of spinal noradrenergic nerve terminals. Perfusion of spinal cord slices with 5'-N-ethylcarboxamide adenosine resulted in a concentration-dependent increase in norepinephrine release. CONCLUSION: These data support clinical examination of intrathecal adenosine alone and with clonidine in the treatment of chronic pain states that include a component of mechanical hypersensitivity and suggest that, after nerve injury, adenosine acts to reduce hypersensitivity through spinal norepinephrine release.