The Differential Roles Of Metabotropic Glutamate Receptors In Bee Venom-induced Nociception And Inflammation In Rats

Background: Inflammation caused by peripheral tissue injures produces pain-related behavior (persistent spontaneous nociception and hyperalgesia ) and inflammatory reaction such as redness,edema. Our previous studies have showed that intraplantar (ipl.) injection of bee venom (BV) produced persistent spontaneous nociception (PSN) and hyperalgesia, as well as obvious inflammatory swelling of the injected paw. Within the last decade, the growing evidences have shown that mGluRs play a key role in the pain and inflammation induced by tissue and nerve injuries.Objective: The present study aims to determine the roles of metabotropic glutamate receptors (mGluRs) in BV-induced nociception and inflammation, by observing the effect of ipl. injection or intrathecal administration of group I mGluR antagonist AIDA, gourp II mGluR agonist ADPC, and group III mGluR agonist L-AP4 on BV-induced PSN, mechanical hyperalgesia, and inflammatory swelling.Methods: We used BV-induced pain rat model to investigate the role of mGluRs in the PSN, mechanical hyperalgesia and inflammation reaction of the injected hind paw. The experiments were performed on Sprague-Dawley albino male rats weighing from 250~300g. Group I mGluR antagonist AIDA, gourp II mGluR agonist ADPC, and group III mGluR agonist L-AP4 were used in the present study. Pre-treatment with intraplantar or intrathecal injection of AIDA, ADPC, and L-AP4 of different doses were made 10 min prior to BV injection. As control, vehicle (50μl/rat) was administrated 10 min prior to BV injection. To determine whether local injections of these drugs had systemic effects, a separate group of rats received pre-treatment with the highest dose of AIDA, ADPC, and L-AP4 injected into the contralateral hind paw. The 50μl solution volume was used for intraplantar drugs and vehicle treatments in the whole study, while 20μl for intrathecal administration. The spontaneous nocicepive behavioral response of rats was determined by counting the number of paw flinches during each 5 min interval of 1 h time course following injection of BV. Paw withdrawal mechanical threshold (PWMT) of injected hind paws by von Frey filaments was examined at time prior to drugs administration and 4 h after BV injection. Change in paw volume was used as a determinant of the BV-induced inflammatory responses. Based on the principle of Archimedes, the paw volume was measured by water displacement using a plethysmometer (Plethysmometer ZH-YLS-7A, Zheng Hua Bioinstruments Inc., China). Measurements were taken at 10 min prior to and 4 h after the BV injection.Results:(1)The effect of mGluRs antagonist or agonists upon BV-indced spontaneus pain.Compared with control group, pre-treatment with intraplantar injection of selective group I mGluRs antagonist, AIDA (0.5-25μmol) produced a dose-related inhibition of BV-induced spontaneous flinching reflex over the observed 1 hour. Pre-treatment with intraplantar injection of AIDA with the lowest dose (0.5μmol) into ipsilateral hind paw only produced a significant inhibition of BV-induced spontaneous flinching reflex in the late phase (26-60 min), but not in the early phase (0-25 min), compsared with control group. Similarly, pre-treatment with intraplantar injection of group II mGluRs agonist ADPC (1-50 nmol), and group III mGluRs agonist L-AP4 (0.2-20μmol) into ipsilateral hind paw produced a significant inhibition of BV-induced spontaneous flinching reflex over the observed 1 hour, but the inhibitory effect is not dose-related. All contralateral drugs treatment had no effect on BV-induced spontaneous flinching reflex, ruling out the systemic effect of these drugs.Pre-treatment with intrathecal administration of AIDA and ADPC significantly inhibited BV-induced PSN compared with vehicle groups. However, pre-treatment with intrathecal administration L-AP4 had no influence on BV-induced spontaneous flinching reflex.(2)The effect of mGluRs antagonist or agonists upon BV-induced hyperalgesia.Compared with control group, pre-treatment with intraplantar injection of group II mGluRs agonist ADPC of higher doses (10 nmol, 50 nmol) into hind ipsilateral paw produced a significant prevention of BV-induced decrease in PWMT, but the lowest dose of ADPC had no effect. However, pre-treatment with intraplantar injection of group I mGluRs antagonist AIDA or group III mGluRs agonist L-AP4 of different doses into ipsil. hind paw had no any inhibitory effect on BV-induced decrease in PWMT, compared with control group. All contralateral drugs treatment had no effect on BV-induced decrease in PWMT, ruling out the systemic effect of these drugs.Compared with vehicle group, pre-treatment with intrathecal administration of AIDA, ADPC, and L-AP4 had no effect on BV-induced hyperalgesia.(3)The effect of mGluRs antagonist or agonists upon BV-indced inflammationCompared with control group, pre-treatment with intraplantar injection of AIDA, ADPC, and L-AP4 of different doses into ipsilateral or contralateral hind paws had no effect on BV-induced increase in paw volume. Pre-treatment with intrathecal administration of AIDA, ADPC, and L-AP4 also had no effect on BV-induced paw volume.Conlusion:(1)Peripheral group I-III mGluRs may contribute to BV-induced PSN, while central group I and II mGluRs may contribute to BV-induced PSN, but group III mGluRs may not be involved in BV-induced PSN.(2)Only peripheral group II mGluRs may be involved in BV-induced mechanical hyperalgesia.(3)Peripheral and central group I-III mGluRs could not play a key role in the development of BV-induced inflammation.