tumor necrosis factor regulates the gene for brain-derived neurotrophic factor (bdnf) in rat...

ciceptive activity of a series of newly synthesized N-substituted cyclic dermorphin/deltorphin tetrapeptideanalogues after systemic application revealed strongerthan morphine (MF) effect induced by analogue con-taining C-terminal ureidoethylamid {[H-Tyr-D-Lys-(&1)-Phe-Dab(&2)-CH2CH2NHCONH2][&1CO&2]}(cUP-1) in hot plate and tail flick tests. The aim of thecurrent study was further evaluation of antinocicep-tive effect of cUP-1 in the models of somatic and vis-ceral pain.

Experiments were performed on male BALB/c miceand Wistar rats. We evaluated the influence of cUP-1(0.5–2 mg/kg, iv) on nociceptive threshold to mechani-cal stimulus (Randall-Selitto test) and its analgesic effi-cacy in the model of persistent (formalin test) and vis-ceral pain (acetic acid induced writhing test). The effectof cUP-1 was compared to that of MF.

In Randall-Selitto test cUP-1 administered in the 1and 2 mg/kg dose elicited significant increase of no-ciceptive threshold to mechanical pressure at 30 and60 min after injection. MF induced significant andsimilar to cUP-1 effect in the higher dose only. In thewrithing test and both phases of formalin test cUP-1applied in the 0.5, 1 and 2 mg/kg dose shown signifi-cant, dose-dependent antinociceptive effect which didnot markedly differ from that of MF.

Systemic application of cUP-1 elicited dose-dependent analgesic activity in acute and persistentpain models. The effect of cUP-1 on visceral and per-sistent somatic pain was comparable to MF, but morepotent on mechanical nociception.

Supported by Ministry of Science and Higher Education.Grant No. OR00004208.

Tumor necrosis factor regulates the gene for brain-derivedneurotrophic factor (BDNF) in rat trigeminal ganglion neuronsEwa Ba³kowiec-Iskra1,2, Olga Kuzawiñska1, Agnieszka Ba³kowiec2

�Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Krakowskie Przedmieœcie 26/28,PL 00-927 Warszawa, Poland; �Department of Integrative Biosciences, Oregon Health and Science University,3181 S.W. Sam Jackson Park Rd., 97239-3098 Portland, Oregon, USA

Many peripheral targets of trigeminal neurons consti-tute the source of common chronic pain conditions,such as migraine headaches, trigeminal neuralgias andtemporomandibular disorders. The trigeminal system,with first-order neurons in the trigeminal ganglion(TG), provides sensory innervation to the majority ofcraniofacial tissues. Although it is well established thatchronic trigeminal pain is frequently associated withinflammation of peripheral endings of TG neurons, theexact molecular mechanisms of trigeminal nociceptivetransmission during inflammatory disorders are stillpoorly understood. Brain brain-derived neurotrophicfactor (BDNF) has been shown in our previous studiesto be upregulated in TG neurons during tooth pulp in-flammation. However, the molecular mechanisms ofBDNF upregulation remain unknown. The goal of thepresent study was to examine the effects of proinflam-matory cytokines on regulation of the BDNF gene inTG neurons using an in vitro model.

Newborn rat TG neurons were grown underneuron-enriched conditions for 3–5 days, followed bytreatment with various pro-inflammatory cytokines,including tumor necrosis factor (TNF), interleukin-1�

(IL-1�), and interleukin-6 (IL-6). The cytokine treat-ment (4 and 24 h) was combined with patterned elec-trical field stimulation to mimic activity of trigeminalneurons in vivo. At the end of the treatment period,cultures were processed for either quantitative PCR orELISA to evaluate changes in BDNF mRNA andprotein, respectively. Our results indicate that TNF-mediated regulation of BDNF transcripts is promoter-specific and dose-dependent, and the effects are sig-nificantly enhanced in the presence of electricalstimulation. In view of the previous evidence thatBDNF is expressed at trigeminal nociceptive syn-apses in the brainstem, presented results point toBDNF as a likely key player of trigeminal inflamma-tory pain.

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International Congress of the Polish Pharmacological Society�������