Spinal cord lesion after long-term intrathecal clonidine and bupivacaine treatment for the management of intractable pain

Long-term intrathecal drug administration using implanted pumps is increasingly used in the treatment of chronic refractory pain [Anderson and Burchiel 1999, Neurosurgery 44 (1999) 289; Krames 2002, Best Pract Res Clin Anaesthesiol 16 (2002) 619; Wallace 2002, Neurology 59 (2002) S18]. Extensive clinical experience over the last 15 years suggests that in selected cases the technique is safe, although infections, system malfunction and drug-related complications have been reported. In most cases, drug-related spinal cord injuries have resulted from the compression of a spinal inflammatory mass or abcess rather than from a direct neurotoxic effect. We report on a case of toxic spinal cord lesion occurring after more than 3 years of uneventful continuous infusion of a mixture of bupivacaine and clonidine.     

Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain

Questions have been raised about the potential neurotoxicity of the neuraxial use of ketamine although ketamine and its active enantiomer S(+)-ketamine have been used intrathecally and epidurally (caudally) for the management of perioperative pain and in a variety of chronic pain syndromes. Clinical experience following neuraxial administration of S(+)-ketamine has been documented without reference to local central nervous system toxicity following this approach. In addition, there are no preclinical safety data regarding stability, compatibility, and neurotoxicity on intrathecal use of single S(+)-ketamine or combinations of S(+)-ketamine, morphine, bupivacaine, and clonidine. In the present case, the continuous intrathecal administration of S(+)-ketamine, in combination with morphine, bupivacaine, and clonidine resulted in adequate pain relief in a patient suffering from intractable neuropathic cancer pain. However, postmortem observation of the spinal cord and nerve roots revealed severe histological abnormalities including central chromatolysis, nerve cell shrinkage, neuronophagia, microglial upregulation, and gliosis. Based on our results, neuraxial administration of S (+)-ketamine cannot be recommended for clinical practise before a systematic study of toxicology of neuraxial S(+)-ketamine in animals or humans has been performed.     

Depression, Night Terrors, and Insomnia Associated With Long-Term Intrathecal Clonidine Therapy

Abstract:   Intraspinal clonidine is an effective adjunct to intrathecal/epidural opioid administration. We report a case of neuropathic pain treated with intraspinal analgesics in which depression, insomnia, and night terrors developed in association with intraspinal clonidine.     

Histological findings after long-term infusion of intrathecal ketamine for chronic pain: a case report.

Ketamine, a selective, noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist, is able to alter pain perception at the spinal level. Little clinical data exist on the intrathecal and epidural use of ketamine in chronic pain. Histopathologic findings after intrathecal injection of ketamine with and without preservatives are rarely reported. This outcome was evaluated in a 72-year-old woman with abdominal pain due to cancer who was treated with the intrathecal application of bupivacaine, clonidine, and morphine. We reached satisfactory pain relief with the addition of ketamine to the mixture for 7 days. On postmortem, focal lymphocytic vasculitis close to the catheter injection site was found. This finding has not been described previously after long-term application of ketamine intrathecally. The intrathecal infusion of ketamine with preservative, or the mixture of ketamine, clonidine, morphine, and bupivacaine resulted in isolated lymphocytic vasculitis of the spinal cord and leptomeninges without any clinical signs of neurological deficit.     

Clonidine maintains intrathecal self-administration in rats following spinal nerve ligation

Clonidine is approved for spinal administration against neuropathic pain, and reverses both spontaneous and elicited pain in humans following spinal administration. Rodent studies that seek to model pharmacology in pain states have historically relied on reflexive withdrawal from noxious stimuli as the primary endpoint. Drug self-administration studies have face validity in the drug abuse field for modeling drug abuse in humans, however, this methodology has not been applied to address issues related to drug seeking behaviors that may be relevant for other human populations, such as patients with neuropathic pain. Rats without spinal nerve ligation (SNL) failed to acquire intrathecal clonidine self-administration over 10 days of access. Rats were found to self-administer intrathecal infusions of clonidine following SNL in a stable and dose-responsive manner, however, and clonidine was self-administered throughout the day with 66% of total drug intake occurring during the dark cycle. Substitution of clonidine with saline or with clonidine and the alpha2-adrenoceptor antagonist idazoxan resulted in extinction of responding in SNL animals. Food reinforcement was initially decreased in SNL rats self-administering clonidine compared to normal animals, however, tolerance developed to this effect of clonidine in SNL rats after 5 days. These data demonstrate that drug self-administration can be applied to questions other than drug abuse, and provides an additional measure for development of novel therapeutic strategies for chronic pain treatment.     

Relative potency of epidural to intrathecal clonidine differs between acute thermal pain and capsaicin-induced allodynia

Clonidine is approved in the US for epidural administration in the treatment of intractable neuropathic cancer pain, but is also administered intrathecally for this indication and both epidurally and intrathecally in the treatment of acute, postoperative pain. The purpose of the current study was to estimate the relative potency of clonidine by epidural and intrathecal routes in the treatment of capsaicin-induced hyperalgesia and allodynia as a model of central hypersensitivity and of noxious heat as a model of acute pain. Twenty-four healthy volunteers were randomized to receive either intrathecal clonidine (75, 150, or 300 micrograms) or epidural clonidine (150, 300, or 600 micrograms) and rated pain from a Peltier-controlled thermode at a lumbar, thoracic, and cervical dermatomal site before and after drug administration. In addition, they rated pain from intradermal capsaicin injections at a lumbar dermatome before and 60 min after clonidine injection and described areas of hyperalgesia and allodynia to mechanical stimuli. Clonidine's effect differed with route of administration and modality of sensory testing. For acute thermal pain, intrathecal clonidine produced a dose-dependent analgesia with a lumbar>thoracic>cervical gradient, whereas only one dose of epidural clonidine reduced thermal pain and this was at the thoracic testing site. In contrast, the potency of clonidine to reduce capsaicin-induced allodynia was similar between the two routes of injection, and for hyperalgesia, clonidine was only slightly more potent after intrathecal than epidural injection. These data support clinical studies from non-comparative trials and suggest there is a >6-fold potency ratio of intrathecal:epidural administration of clonidine for acute pain, but a <2-fold potency ratio for these routes for mechanical hypersensitivity.     

Spinal cord pharmacology of adrenergic agonist-mediated antinociception

Intrathecal administration of norepinephrine (NE) and alpha adrenergic agonists in rats with chronic spinal catheters produced a significant elevation of the nociceptive threshold as measured by hot plate and tail flick. The intrathecal NE effect was dose-dependent and antagonized in a competitive fashion by pretreatment with phentolamine (alpha antagonist) but not by propranolol (beta antagonist). Intrathecal administration of isoproterenol (beta agonist) did not alter the nociceptive threshold. Effective doses of intrathecal NE did not produce demonstrable motor effects. Doses 20 times greater than the maximum analgesic dose produced marked weakness of the hindlimbs and tails. The intrathecal NE effect was not antagonized by intrathecal papaverine of bradykinin (vasodilators) or mimicked by angiotensin-II (vasoconstrictor). The intrathecal NE effect was not altered by intrathecal administration of subconvulsant doses of either picrotoxin (gamma-aminobutyric acid antagonist) or strychnine (glycine antagonist) or by i.p. administration of either naloxone (opiate antagonist) or methysergide (serotinin antagonist). The nociceptive threshold was significantly decreased 1 week after intrathecal administration of 6-hydroxydopamine, which depleted spinal cord NE by 85%. Intrathecal administration of tyramine (indirectly acting sympathomimetic amine) produced an elevation of the nociceptive threshold in a control group of animals but was less effective in animals pretreated with intrathecal 6-hydroxydopamine. The tyramine effect was antagonized by intrathecal phentolamine. Intravenous administration of aminophylline (phosphodiesterase inhibitor) did not potentiate the intrathecal NE effect. The relative antinociceptive potencies of alpha adrenergic agonists after intrathecal administration were: l-norepinephrine = dl-epinephrine greater than dl-alpha-methyl norepinephrine greater than clonidine greater than or equal to l-phenylephrine greater than or equal to 3,4-dihydroxytolazoline greater than or equal to oxymetazoline. The relative potencies of intrathecally administered alpha antagonists in antagonizing the intrathecal NE effect were: phentolamine greater than phenoxybenzamine greater than tolazoline greater than or equal to yohimbine.     

Role of calcium channels in the spinal transmission of nociceptive information from the mesentery

Opioids, alpha(2)-adrenoceptor agonists and blockers of voltage-gated calcium channels (VGCCs) have been attributed antinociceptive activity in various experimental set-ups. The present study tested the ability of morphine, clonidine and drugs acting at various VGCCs to inhibit the transmission of noxious stimuli from the mesentery at the level of the spinal cord. In rats under barbiturate anaesthesia traction of 20 g was applied to a bundle of mesenteric blood vessels. This caused immediate transient changes of mean arterial pressure that were taken as indication of nociception. Similar reflexes were elicited by applying 0.6% acetic acid to the same bundle of vessels. The reflexes were dose-dependently reduced by intrathecal administration of morphine or clonidine, but were left unaltered by intrathecal administration of verapamil, Bay-K 8644 or omega-conotoxin MVIIA. Neither verapamil nor Bay-K 8644 influenced clonidine-induced analgesia. Conotoxin markedly enhanced the effectiveness of all doses of clonidine against both types of mesenteric stimuli. Verapamil, Bay-K 8644, as well as conotoxin reduced the ability of morphine to inhibit mechanically evoked reflexes, while there was no statistically significant effect in chemonociception. These data suggest that, at the spinal level, both morphine and clonidine are effective drugs to decrease the cardiovascular changes caused by acute mesenteric pain. In the dorsal spinal cord neither L-type nor N-type VGCCs are responsible on their own for the transmission of noxious stimuli from the mesentery. Inhibition of N-type channels markedly augments the action of clonidine, whereas blocking either VGCC seems to inhibit antinociceptive mechanisms induced by morphine. It is suggested that in patients the combined administration of clonidine with omega-conotoxin MVIIA might lead to effective pain control with reduced side effects.     

Intrathecal Drug Administration in Chronic Pain Syndromes

Chronic pain may recur after initial response to strong opioids in both patients with cancer and patients without cancer or therapy may be complicated by intolerable side effects. When minimally invasive interventional pain management techniques also fail to provide satisfactory pain relief, continuous intrathecal analgesic administration may be considered. Only 3 products have been officially approved for long‐term intrathecal administration: morphine, baclofen, and ziconotide. The efficacy of intrathecal ziconotide for the management of patients with severe chronic refractory noncancer pain was illustrated in 3 placebo‐controlled trials. A randomized study showed this treatment option to be effective over a short follow‐up period for patients with pain due to cancer or AIDS. The efficacy of intrathecal opioid administration for the management of chronic noncancer pain is mainly derived from prospective and retrospective noncontrolled trials. The effect of intrathecal morphine administration in patients with pain due to cancer was compared with oral or transdermal treatment in a randomized controlled trial, which found better pain control and fewer side effects with intrathecal opioids. Other evidence is derived from cohort studies. Side effects of chronic intrathecal therapy may either be technical (catheter or pump malfunction) or biological (infection). The most troublesome complication is, however, the possibility of granuloma formation at the catheter tip that may induce neurological damage. Given limited studies, the evidence for intrathecal drug administration in patients suffering from cancer‐related pain is more compelling than that of chronic noncancer pain.     

An isobolographic analysis of the antinociceptive effect of systemically and intrathecally administered combinations of clonidine and opiates

The antinociceptive interaction of opiate analgesics with clonidine was examined with the tail-flick and 55 degrees C hot plate tests. Male Sprague-Dawley rats received fixed ratios of clonidine to fentanyl, meperidine or morphine by i.v. and intrathecal injection. Data are expressed as percentage of maximal possible effect and the dose producing 50 percentage of maximal possible effect for each drug or drug combination is used to index potency. The rank order of potency in both tests after i.v. administration is fentanyl much greater than clonidine greater than meperidine greater than or equal to morphine and after intrathecal administration it is morphine greater than fentanyl much greater than clonidine much greater than meperidine. Isobolographic analysis shows that the effect of clonidine combined with an opiate is additive after i.v. administration; the exception is that morphine and clonidine are synergistic in the hot plate test. The intrathecal combinations of clonidine with morphine or meperidine produces a supra-additive antinociceptive effect in the tail-flick test but not in the hot plate test. Fentanyl does so in both tests. These data confirm a positive interaction between clonidine and opiates in producing antinociception. This interaction may be additive or synergistic, depending on route of administration and the nociceptive test used. The timing of injections and pharmacokinetic factors may also influence the results. Moreover, these results suggest that the interaction between the opiate and alpha-2 adrenergic receptors occurs within the spinal cord.     

Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome

Activated immune cells in the spinal cord may play an important role in the development and maintenance of neuropathic pain, such as occurs in response to peripheral inflammation or tissue injury. Immune activation may therefore serve as a therapeutic target for immune modulating drugs like corticosteroids. This double-blind randomized placebo-controlled parallel-group trial aimed to investigate the efficacy and safety of a single intrathecal administration of 60 mg methylprednisolone (ITM) in chronic patients with complex regional pain syndrome (CRPS). The primary outcome measure was change in pain (pain intensity numeric rating scale; range 0–10) after 6 weeks. With 21 subjects per group the study had a 90% power to detect a clinically relevant difference (?2 points). After 21 patients (10 on ITM) were included, the trial was stopped prematurely after the interim analysis had shown that ITM had no effect on pain (difference in mean pain intensity numeric rating scale at 6 weeks 0.3, 95% confidence interval ?0.7 to 1.3) or any other outcome measure. We did not find any difference in treatment-emergent adverse events between the ITM and placebo group. We conclude that a single bolus administration of ITM is not efficacious in chronic CRPS patients, which may indicate that spinal immune activation does not play an important role in this phase of the syndrome.     

Spinal administration of alpha 2-adrenoceptor agonists and opioids or local anaesthetic agents

The effects of combined spinal administration of alpha(2)-adrenoceptor agonists, local anaesthetics, and opioids have been extensively studied. The motor and the sensory block of spinal and epidural anaesthesia is enhanced and prolonged by the combination of clonidine with the local anaesthetics lidocaine, tetracaine and bupivacaine. Because higher plasma levels of local anaesthetics were measured when clonidine was injected epidurally, the enhancement of the local anaesthetic's effect by clonidine is not due to slowed resorption, but rather to direct spinal and supraspinal effects of clonidine. Furthermore, direct local anaesthetic properties of clonidine on nerve fibres are discussed. In addition, in children the combination of clonidine and bupivacaine for caudal anaesthesia resulted in a marked prolongation of postoperative pain relief. Circulatory effects of combined clonidine and local anaesthetics are the result of the specific spinal blockade and the central and peripheral effects of clonidine. The combined epidural and intrathecal administration of opioids and alpha(2)-adrenoceptor agonists provides better postoperative pain relief than the administration of either substance alone. In humans, the interaction seems to be additive rather than supra-additive. Because of its limited duration of action, continuous administration of clonidine is recommended, especially when it is used in combination with opioids. Neither the incidence nor the severity of side effects is increased by a combined therapy with opioids. Despite the sedative properties of clonidine, there is no increased risk of respiratory depression when clonidine is given in combination with opioids. The inhibiting effect on the sympathetic nervous system activity regularly observed during spinal administration of clonidine supports the value of this therapy and will support its use in the future. Therefore, the combination of alpha(2)-adrenoceptor agonists with local anaesthetics or opioids is reasonable and may improve anaesthetic practice.     

Effects of Intravenous Small Dose Ketamine and Midazolam on Postoperative Pain Following Knee Arthroscopy

Background:   The aim of this randomized, double blind, controlled study was to assess the effect of intravenous coadministration of small dose midazolam with ketamine on postoperative pain and spinal block level.
Methods:   Sixty patients undergoing arthroscopic knee surgery under spinal anesthesia were randomized into three groups: Group I (saline control); group II (ketamine 0.15 mg/kg i.v.); and group III (ketamine 0.15 mg/kg +  midazolam 0.01 mg/kg i.v.). Sedation scores, visual analogue scores, time to first postoperative analgesic, total meperidine consumption, patient satisfaction, sensory and motor block levels, and two segments regression times were assessed.
Results:   Sedation scores were significantly lower in group I when compared with groups II and III at 1, 3, 5, and 10 minutes after administration of the spinal anesthetic ( P  = 0.001). Sensory block was significantly higher in group III ( P  = 0.001) in comparison with group II. Two segment regression time was significantly longer in group II than group I, whereas no difference was found between groups II and III. Total meperidine consumption was significantly higher in group I ( P  = 0,001). Patient satisfaction was significantly higher in group III compared with group I ( P  = 0.001), but no difference was found between groups II and III ( P  = 0.3).
Conclusion:   Ketamine improved the postoperative pain patient satisfaction, increased the maximal sensory level, and was associated with lower sedation scores in the first 15 minutes after administration. Group I was also associated with decreased total meperidine consumption and delayed the time to first recue analgesic administration. Coadministration of ketamine and midazolam did not provide any further benefit over ketamine alone.     

Neuraxial pain relief for intractable cancer pain

Most patients with cancer pain achieve good analgesia using traditional analgesics and adjuvant medications; however, an important minority of patients (2% to 5%) suffers from severe and refractory cancer pain. For these individuals, spinal analgesics (intrathecal or epidural) provide significant hope for pain relief over months or years of treatment to help improve quality of life. Spinal analgesics have been suggested as the fourth step in the World Health Organization guidelines in the management of cancer pain, and thus the pain physician should be familiar with principles of use. Most patients achieve pain relief using spinal analgesics, with a minimum of complications that are easily managed at home. A variety of opioids, local anesthetics, clonidine, ketamine, and other analgesics are available for the spinal route of administration and should be titrated to clinical effect or intolerable side effect. This article discusses the appropriate selection of patients for spinal analgesics, reviews current recommended infusion systems and current spinal analgesics, discusses possible complications, and includes practical suggestions for patient management.     

Biochemical and clinical aspects of methotrexate neurotoxicity

Acute, subacute and chronic neurotoxicity have been observed after the administration of high-dose and/or intrathecal methotrexate (MTX). Acute toxicity is usually transient without permanent damage. Subacute and chronic toxicity are associated with changes in the brain and/or the spinal cord which may be progressive and even lead to coma and death in severe cases. It is believed that MTX can induce direct toxic effects to the CNS by damaging the neuronal tissue. Moreover, MTX interferes with the metabolic pathways of folates, excitatory amino acids, homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, adenosine and biopterins, inducing biochemical alterations which have been associated with neurotoxic symptoms. It has been suggested that acute toxicity is partly mediated by adenosine, whereas homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, excitatory amino acids and biopterins may play an important role in the development of subacute and chronic toxicity. A better understanding of the pathogenesis of MTX neurotoxicity would offer the possibility of developing new therapeutic strategies for its treatment or prevention.     

Neurotoxicity of midazolam in the rabbit

Safe and efficient use of spinal drugs requires neurotoxicologic animal studies before ethical application. We have evaluated the neurotoxicologic interruptions of intrathecal administration of midazolam in rabbits. Eighteen white New Zealand rabbits were randomly assigned into three groups consisting of six rabbits each. In conscious animals, 0.3 ml 0.9% normal saline solution, 0.3 ml 0.1% midazolam (Roche, Dormicum) or 0.3 ml preservative free midazolam were intrathecally administered. Light and fluorescence microscopy evaluations were performed on transverse spinal cord sections by a neurohistopathologist in a blind fashion. Midazolam and preservative free midazolam treated rabbits showed significant histologic changes in light and fluorescence microscopy. The histologic and vascular lesions with the use of midazolam and preservative free midazolam suggested neurotoxic effects; thus chronic intrathecal administration of midazolam should be avoided in humans.     

Failed Back Surgery Syndrome and intrathecal drugs infusion

Even if there is no study evaluating how often Failed Back Surgery Syndrome is the cause of pain in patients who need spinal drugs infusion to control their symptoms, it seems that in most centres, Failed Back Surgery Syndrome was the most frequent indication for spinal cord stimulation and for intrathecal analgesic delivery pumps implantation. In our experience of spinal drug delivery for pain, about one third of the patients (35.7%) had undergone one or more spinal surgeries.A literature search was performed looking for intrathecal drugs infusion and Failed Back Surgery Syndrome or chronic back and leg pain without specification of previous surgery. The data in which we were interested were trialling methods, drugs used, outcomes and side effects. A comparison was made with the 14 years experience in intrathecal drugs infusion in our centre.We evaluated the side effects reported with chronic spinal drugs infusion even if not specific for patients with Failed Back Surgery Syndrome.     

Acupoint Stimulation With Diluted Bee Venom (Apipuncture) Potentiates the Analgesic Effect of Intrathecal Clonidine in the Rodent Formalin Test and in a Neuropathic Pain Model

Although intrathecal (i.t.) administration of the α₂-adrenoceptor agonist clonidine has a pronounced analgesic effect, the clinical use of clonidine is limited by its side effects. Previously, our laboratory has demonstrated that the subcutaneous injection of diluted bee venom (DBV) into an acupoint (termed apipuncture) produces significant analgesic effect in various pain animal models. The present study was designed to examine whether DBV injection into the Zusanli acupoint (ST-36) could enhance lower-dose clonidine-induced analgesic effects without the development of hypotension, bradycardia, or sedation. In the mouse formalin test, DBV injection produced a dramatic leftward shift in the dose-response curve for clonidine-induced analgesia. In a rat neuropathic pain model i.t. clonidine dose dependently suppressed chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia, and this clonidine-induced analgesic effect was significantly potentiated by apipuncture pretreatment. DBV apipuncture alone or in combination with a low dose of i.t. clonidine produced an analgesic effect similar to that of the high dose of clonidine, but without significant side effects. The analgesic effect produced by the combination of i.t. clonidine and apipuncture was completely blocked by pretreatment with an α₂-adrenoceptor antagonist. These data show that DBV-apipuncture significantly enhances clonidine-induced analgesia and suggest that a combination of low dose clonidine with acupuncture therapy represents a novel strategy for pain management that could eliminates clonidine's side effects.PerspectiveThis study demonstrated that intrathecal clonidine-induced analgesia is significantly enhanced when it is combined with chemical acupuncture treatment. The administration of low-dose clonidine in combination with acupuncture produced a potent analgesic effect without significant side effects and thus represents a potential novel strategy for the management of chronic pain.     

The antinociceptive activity of intrathecally administered amiloride and its interactions with morphine and clonidine in rats

In this study, we aimed to evaluate the antinociceptive interaction between intrathecally administered amiloride and morphine or clonidine. Using rats chronically implanted with lumbar intrathecal catheters, we examined the ability of intrathecal amiloride, morphine, clonidine, and mixtures of amiloride-morphine and amiloride-clonidine to alter tail-flick latency. To characterize any interactions, isobolographic analysis was performed. The effects of pretreatment with intrathecally administered naloxone or yohimbine were tested. Intrathecal administration of amiloride (25-150 μg), morphine (.25-10 μg), or clonidine (.5-10 μg) alone produced significant dose-dependent antinociception in the tail-flick test. The median effective dose (ED(50)) values for intrathecally administered amiloride, morphine, and clonidine were 120.5 μg, 5.0 μg, and 4.4 μg, respectively. Isobolographic analysis exhibited a synergistic interaction after coadministration of amiloride-morphine and amiloride-clonidine. Intrathecal pretreatment with naloxone (10 μg) completely blocked the antinociceptive effects of morphine and the amiloride-morphine mixture. Intrathecal pretreatment with yohimbine (20 μg) completely blocked the antinociceptive effect of clonidine and antagonized the effect of the amiloride-clonidine mixture. There was no motor dysfunction or significant change in blood pressure or heart rate after the intrathecal administration of amiloride, amiloride-morphine, and amiloride-clonidine. The synergistic effect observed after the coadministration of amiloride and morphine or clonidine suggests a functional interaction among calcium channels, μ-receptors and α(2)-receptors at the spinal cord level of the nociceptive processing system. PERSPECTIVE: Although intrathecal morphine and clonidine produces pronounced analgesia, antinociceptive doses of intrathecal morphine and clonidine produce several side effects, including hypotension, bradycardia, sedation, and tolerance. This article presents antinociceptive synergistic interaction between amiloride and morphine, amiloride, and clonidine on thermal nociceptive tests in the rat.     

Intrathecal AAV Serotype 9-mediated Delivery of shRNA Against TRPV1 Attenuates Thermal Hyperalgesia in a Mouse Model of Peripheral Nerve Injury

Gene therapy for neuropathic pain requires efficient gene delivery to both central and peripheral nervous systems. We previously showed that an adenoassociated virus serotype 9 (AAV9) vector expressing short-hairpin RNA (shRNA) could suppress target molecule expression in the dorsal root ganglia (DRG) and spinal cord upon intrathecal injection. To evaluate the therapeutic potential of this approach, we constructed an AAV9 vector encoding shRNA against vanilloid receptor 1 (TRPV1), which is an important target gene for acute pain, but its role in chronic neuropathic pain remains unclear. We intrathecally injected it into the subarachnoid space at the upper lumbar spine of mice 3 weeks after spared nerve injury (SNI). Delivered shTRPV1 effectively suppressed mRNA and protein expression of TRPV1 in the DRG and spinal cord, and it attenuated nerve injury-induced thermal allodynia 10–28 days after treatment. Our study provides important evidence for the contribution of TRPV1 to thermal hypersensitivity in neuropathic pain and thus establishes intrathecal AAV9-mediated gene delivery as an investigative and potentially therapeutic platform for the nervous system.