Henri Dr. Doods

The bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons.

Bradykinin is a neuropeptide released after tissue damage which plays an important role in inflammatory pain. The up‐regulation of the bradykinin B1 receptor in response to inflammation makes it an attractive target for drug development. Aim was to investigate if the selective B1 receptor antagonist BI113823 reduces inflammation‐induced mechanical hyperalgesia and if the effect is mediated via peripheral and/or spinal B1 receptor antagonism.

Electrophysiological characterization of spinal neurons in different models of diabetes type 1- and type 2-induced neuropathy in rats.

Diabetic polyneuropathy (DPN) is a devastating complication of diabetes. The underlying pathogenesis of DPN is still elusive and an effective treatment devoid of side effects presents a challenge. There is evidence that in type-1 and -2 diabetes, metabolic and morphological changes lead to peripheral nerve damage and altered central nociceptive transmission, which may contribute to neuropathic pain symptoms. We characterized the electrophysiological response properties of spinal wide dynamic range (WDR) neurons in three diabetic models. The streptozotocin (STZ) model was used as a drug-induced model of type-1 diabetes, and the BioBreeding/Worcester (BB/Wor) and Zucker diabetic fatty (ZDF) rat models were used for genetic DPN models. Data were compared to the respective control group (BB/Wor diabetic-resistant, Zucker lean (ZL) and saline-injected Wistar rat). Response properties of WDR neurons to mechanical stimulation and spontaneous activity were assessed. We found abnormal response properties of spinal WDR neurons in all diabetic rats but not controls. Profound differences between models were observed. In BB/Wor diabetic rats evoked responses were increased, while in ZDF rats spontaneous activity was increased and in STZ rats mainly after discharges were increased. The abnormal response properties of neurons might indicate differential pathological, diabetes-induced, changes in spinal neuronal transmission. This study shows for the first time that specific electrophysiological response properties are characteristic for certain models of DPN and that these might reflect the diverse and complex symptomatology of DPN in the clinic.

164 ANXIETY-LIKE BEHAVIOUR IS OBSERVED IN TWO RAT MODELS OF MONONEUROPATHY

administration. The reversal of tactile allodynia was maintained with repeated administration for 5 days. Similar reversal of tactile allodynia was seen in a model of vincristine-induced neuropathic pain. In addition, long term treatment with TRO19622 normalized motor nerve conduction in diabetic rats suggesting that this compound may improve neuropathic syndromes in addition to analgesic activity. By contrast, TRO19622 did not reverse thermal hyperalgesia in normal or neuropathic rats or pain-like behaviour in the formalin test. These data suggest that TRO19622 specifically reverses neuropathic rather than noxious or inflammatory pain. Even at very high doses TRO19622 is devoid of sedative or other adverse effects of current analgesics and therefore offers a promising new approach for treating neuropathic pain. A Phase 2 study in diabetic neuropathic pain is currently ongoing.

151 Mononeuropathic animals displayed depressive-like behaviour in the model of forced swimming test

The amygdala (AMY) has an important role in emotional responses to pain. It receives nociceptive inputs from the periphery and central modulatory influence from various limbic sites, including the anterior cingulate cortex (ACC). The influence of chronic neuropathy on response properties of AMY neurons and their central modulation is still only poorly known. We determined the response characteristics of AMY neurons to noxious peripheral stimulation and their central modulation by the ACC in a spared nerve injury (SNI) model of peripheral neuropathy in the rat. Moreover, in order to determine have behavioral correlates for neuronal findings, mechanically evoked spinal withdrawal responses and aversion behavior were recorded. Recordings of AMY neurons were performed in anesthetized SNI and shamoperated animals. Peripheral noxious stimuli consisted of heating and cooling, mechanical skin stimulation and colorectal distension. Furthermore, central modulation of AMY neurons was studied by injecting glutamate or an NMDA receptor antagonist into the ACC. The SNI group had a markedly reduced spinal withdrawal threshold to mechanical stimulation that was associated with a strong aversion-like response to light tactile stimulation. SNI produced changes in peripherally evoked neuronal responses that varied depending on the modality of stimulation and the recording site in the AMY. Moreover, glutamatergic modulation of AMY neurons from the ACC was changed in the SNI group. The results indicate that chronic neuropathy induces plastic changes in peripherally evoked responses and central modulation of AMY neurons. These neuronal changes are associated with behavioral changes reflecting allodynia-like spinal reflex and affective symptoms.

Behavioural, morphological and electrophysiological assessment of the effects of type 2 diabetes mellitus on large and small nerve fibres in Zucker diabetic fatty, Zucker lean and Wistar rats

Peripheral neuropathy is a common complication in type 2 diabetes mellitus (T2DM). The most common presentation is in the form of a distal axonal sensory‐motor polyneuropathy that involves large and small nerve fibres in variable proportion.

383 DULOXETINE, BUT NOT FLUOXETINE, ATTENUATES DEPRESSION-LIKE BEHAVIOR IN ANIMALS WITH CHRONIC NEUROPATHIC PAIN

dorsal horn. Neuropathic pain was modelled by selectively tying off left L5 and L6 spinal nerves (control rats underwent sham surgery). Paw withdrawal responses to mechanical stimuli were assessed on post-operative days 7 and 14, and thereafter in vivo electrophysiological responses of contralateral spinal dorsal horn neurones to peripheral stimuli were tested before and after the systemic injection of 10mg/kg and 30mg/kg pregabalin. Behavioural signs of hypersensitivity were ipsilaterally restricted in nerve-injured rats. Electrophysiological testing revealed no significant alterations in the pre-drug responses of contralateral dorsal horn neurones relative to those observed in sham animals, and these responses were not inhibited in either animal by PGB. Hence, increased bilateral activation of descending serotonergic controls following nerve injury is insufficient to induce a sensitised state in the spinal cord. The strict ipsilateral efficacy of PGB must require neuropathy-induced spinal changes acting in concert with descending facilitations to restrict global spinal sensitisation.

385 ASSESSMENT OF MECHANICAL ALLODYNIA: GLASS VS NYLON VON FREY FILAMENTS

Several evidences indicate that spinal gabaergic interneurons and/or GABA receptors can be activated by descending systems of supra-spinal origin, which primarily descend via the dorsolateral funiculus (DLF). The reduction of the inhibitory control exerted by spinal gabaergic system and the changes in the activity of mechanisms that control nociception may be important processes related to emergence and maintenance of allodynia resulting from injury of nerve. This study examines whether DLF lesion changes the anti-allodynic effect of muscimol, baclofen and gabapentine during start and development of mechanica allodynia induced by chronic ligature applied to the L5/L6 spinal nerves. The mechanica allodynia was evaluated using an electronic anesthesiometer. Drug or vehicle was administered intrathecally via a catheter implanted chronically in the subarachnoid space. The chronic constriction of nerve reduced the threshold for 21 days, and this phenomenon was completely reversed in DLF lesion animals. Intrathecal baclofen (0.8mg/10mL), muscimol (0.2mg/10mL) or gabapentine (200mg/10mL) reversed the mechanical allodynia, in both 2th and 7th post-surgical day. The anti-allodynic effect of baclofen, but not muscimol or gabapentin, was significantly blocked in animals subjected to DLF lesion. The results indicate that the anti-allodynic effect of baclofen may result from a pre-synaptic inhibition of nerve terminals of brainstem facilitatory neurons that descend via DLF; the anti-allodynic effect of muscimol and gabapentine results from inhibition of nociceptive transmission at the spinal dorsal horn primary afferent neuron and second-order neurons. FAPES and CNPq

288 EFFECT OF THE B1 ANTAGONIST BI 41488 IN DIFFERENT ANIMAL MODELS OF INFLAMMATORY PAIN

Background and Aims: The bradykinin 1 receptor is involved in both the initiation and progression of inflammatory response and pain (Marceau and Regoli, Nature Reviews Drug Discovery, 3, 845, 2004). The aim of this study was to test the B1 antagonist BI 41488 in two animal models of inflammatory pain. Material and methods: Binding affinity studies were performed using CHO cells expressing rat B1 receptors and H-kallidin as radioligand for the rat B1 receptors. Formalin paw test: The total number of flinches was evaluated after injection of formalin (50mL, 2%) into the plantar surface of the hind paw. Carrageenan paw test: Compound was administered 1 hour before carrageenan (50mL, 2%) into the plantar surface of the hindpaw. Mechanical and thermal hyperalgesia were tested 4 hours after carrageenan injection. Results: The affinity of BI 41488 for rat B1 receptors is 19nM. BI 41488, 30mg/kg p.o., 2 hours pre-treatment, significantly reduced the total number of flinches in the formalin paw test (50% effect). In the carraggeenan model, at 30mg/kg p.o., BI 41488 and indomethacin fully reversed mechanical and thermal hyperalgesia. Discussion: BI 41488 displayed a high potency for the rat B1 receptor and is orally active in different animal models of inflammatory pain. These results suggest the therapeutic utility of bradykinin B1 antagonists for the treatment of nociceptive pain.

173 BRADYKININ 1 RECEPTOR STIMULATION INDUCES SENSITIZATION OF VANILLOID 1 NOCICEPTORS – TRPV1 – IN DORSAL ROOT GANGLION CELLS

response was concentration-dependent and showed complete recovery within minutes in most neurons. The percentage of cells responding gradually increased to about 20% at 1 mM CGRP. Tachyphylaxis was observed upon repeated stimulation even at 10 min intervals. The responses could be inhibited by a CGRP receptor antagonist. An intriguing variability in CGRP sensitivity was observed between cultures. The majority of cells was sensitive to capsaicin. Conclusion: A potent CGRP sensitivity of isolated trigeminal sensory neurons was discovered. The determinants of variable CGRP sensitivity deserve further investigation, because CGRP could create a positive feedback through autoreceptors.

314 IN VIVO CHARACTERIZATION OF SELECTIVE TRPV1 ANTAGONIST BCTC IN DIFFERENT ANIMAL MODELS OF ACUTE AND CHRONIC PAIN

in thalamus, basal ganglia, insula, secondary somatosensory cortex (SII) and anterior cingulate cortex (ACC), and in the right cerebellum. The group map from the rotations of the non-painful shoulder demonstrated activity only in contralateral SII and insula. Conclusions: We have shown that movement induced allodynia is measurable using fMRI. Movement induced allodynia in the diseased shoulder activated the pain matrix while the identical range of movement in the normal shoulder did not. Patients are currently being assessed post surgically to determine whether objective fMRI related brain activity changes concur with subjective rating changes.