(617) Refer to Oral Paper Session 330

(618) Effects of lacosamide as compared to other analgesics:A responder analysis in the streptozotocin rat model fordiabetic neuropathic pain

T Stoehr, N Callizot, B Beyreuther; Schwarz BioSciences, Monheim, Germany

Lacosamide (SPM 927; R-2-acetamido-N-benzyl-3-methoxypropi-onamide) also formerly called harkoseride is a novel anticonvulsant drugwith a novel but yet unknown mode of action. Lacosamide has shownactivity in a wide variety of animal models and is currently being evalu-ated in phase III clinical development for the treatment of diabetic neu-ropathic pain. The streptozotocin (STZ)-treated rat model has beenwidely accepted as a model of insulin-dependent diabetes mellitus anda number of anomalies in pain perception have been demonstrated inthis model. It was therefore of interest to profile lacosamide in thismodel in comparison to other anticonvulsants and antidepressants.Since a responder analysis is increasingly used for comparing the resultsof analgesics tested in clinical trials we employed this measure for thiscurrent experiment in rats. Diabetic neuropathic pain was induced byacute administration of streptozotocin (55mg/kg, i.v.). Ten days follow-ing the administration of STZ, tail vein blood was assayed for glucose ineach individual animal. The activity of different anticonvulsants andantidepressants on allodynia and hyperalgesia was investigated in neu-ropathic rats between day 10 and day 21 after treatment with STZ.Treatment response was defined as 50% maximal treatment responsei.e. 50% of pain threshold in healthy control rats minus pain threshold invehicle treated diabetic rats. Lacosamide had a maximal treatment re-sponse of 73%, 93% and 47% for thermal allodynia, mechanical allo-dynia and mechanical hyperalgesia, respectively. Lacosamide had highertreatment responses when compared to amitriptyline, levetiracetam,pregabalin, lamotrigine and venlafaxine except for amitriptyline’s ef-fects on thermal allodynia. Lacosamide has strong antinociceptive activ-ity on all parameters assessed in the STZ rat model for diabetic neuro-pathic pain and seemed to be the compound with the broadest efficacyin inhibiting pain behavior.

(619) Refer to Oral Paper Session 330

(620) Pathophysiological mechanisms underlying cold allo-dynia and mechanical hyperalgesia are different: Evi-dence from a mouse model of neuropathic pain

A-K Gilbert; AstraZeneca R&D Montreal, Montreal, QC, CanadaSociety for Neuroscience abstract

(621) Role of neuromedin U-R2 receptors (NmU-R2) in inflam-matory and neuropathic pain: Behavioural phenotypeof NmU-R2 knockout mice

J Lair; AstraZeneca R&D Montreal, Montreal, QC, CanadaSociety for Neuroscience abstract

(622) Postural asymmetry may contribute to reduced mechan-ical withdrawal thresholds after unilateral nerve injury

E Frakes, J Cutkomp, D Hammond; The University of Iowa, Iowa City, IAAn ipsilateral reduction in mechanical withdrawal thresholds is com-monly reported in rodent models of unilateral nerve injury. It has beenproposed that the tactile allodynia may be exaggerated due to a pos-tural asymmetry of the affected limb, which is often flexed. If true,tactile allodynia should be blunted in models of bilateral nerve injury inwhich postural asymmetry is absent. This study compared the effects ofbilateral and unilateral nerve injury in the spared nerve (SNI) and spinalnerve ligation (SNL) models. Additionally, the tester was asked to iden-tify the condition of the paw based on physical characteristics beforetesting to test the ability to blind to the condition of the animal. MaleSprague-Dawley rats underwent unilateral or bilateral SNI, SNL or bilat-eral sham surgeries under halothane anesthesia. All rats within the SNLand SNI groups had identical surgical incisions. Mechanical thresholdswere determined with von Frey filaments via the up-down method.Bilateral SNL significantly reduced mechanical withdrawal thresholdscompared to sham and naı̈ve rats. However, these values did not differfrom those of unilateral SNL rats. In SNL rats, the tester was able toidentify only 7 of 48 (14.6%) ligated paws, suggesting a successful blind-ing to the condition. In SNI rats, the magnitude of tactile allodynia didnot differ for unilateral or bilateral injury initially. By 2 weeks, a trendbegan that achieved statistical significance by 6 weeks, where by ratswith unilateral SNI exhibited reduced mechanical thresholds comparedto bilateral SNI rats. Moreover, the tester was able to identify 71 of 88(80.7%) ligated paws, suggesting that blinding to surgical status is notpossible in the SNI model. Postural asymmetry is not a factor in themechanical allodynia observed in the SNL model, but may be a factor inthe SNI model at later time points.

(623) Spinal cord gene transfer using naked plasmid DNAcoding the anti-inflammatory gene, Interleukin-10(IL10) leads to long-term reversal of thermal hyperalge-sia in chronic constriction injury (CCI) rats

D Busha, E Milligan, C Murphy, J Mahoney, B Coats, S Langer, L Leinwand,R Chavez, S Maier, L Watkins; University of Colorado, Boulder, COThe pro-inflammatoy cytokine, interleukin-1, released from activatedspinal cord glia are shown to critically mediate the maintenance of lowthreshold mechanical allodynia produced by Chronic Constriction Injury(CCI). The anti-inflammatory cytokine, IL10, suppresses the production &function of proinflammatory cytokines. Spinal delivery (intrathecal; i.t.)viral vectors encoding IL-10 produces a transient reversal of allodynia,whereas naked plasmid DNA encoding IL10 (pDNA-rIL-10) prolongedCCI-induced allodynia for 40 days. Here, we examined both the chronicand acute effects of i.t. pDNA-rIL-10 or control plasmid lacking the rIL-10gene (pDNA-control) to (a) alter pain facilitation assayed by 2 measuresof thermal nociceptive responsivity, the Hargreaves & the tail flick (TF)tests immediately following a single & second injection, and (b) reversethermal hyperalgesia for an extended timecourse (up to 90 days). Allo-dynia (von Frey test) was assessed during the long time-course to verifyprevious observations. Thermal hyperalgesia & allodynia was assessedprior to & 10 days after CCI. Beginning on Day 10, rats received 2 succes-sive i.t. injections spaced 3 days apart. TF & Hargreaves tests were as-sayed at 1,3,6 & 24hr following each injection. Both thermal hyperalge-sia and allodynia was reassessed thereafter until pDNA-rIL-10 resolved.Both pDNA-rIL10 & pDNA-control produced increased TF latencies 1-6 hrpost-injection, suggesting a possible analgesic action of pDNA, andcaused a rapid anti-hyperalgesia by 6hr. However, pDNA-control effectswere transient, lasting only 4-6 days following the 2nd injection,whereas pDNA-rIL10 produced prolonged reversal from thermal hyper-algesia & allodynia lasting greater than 30 days. Ongoing studies areaimed at examining 1) spinal cord & cerebrospinal fluid changes inmRNA for plasmid-derived IL10 & its receptors after i.t. pDNA-rIL10 inbehaviorally verified rats, 2) whether IL10 facilitates gene transcription,& 3) a bimodal action of plasmid therapy. DA018156,DA015642,MH01558, MH00314, NS38020.

S13Abstracts