1 Intrathecal (i.t.) administration of prostaglandin E2 (PGE2) to conscious mice induced allodynia, a state of discomfort and pain evoked by innocuous tactile stimuli, and hyperalgesia as assessed by the hot plate test. We characterized prostaglandin E receptor subtypes (EP,-3) involved in these sensory disorders by use of 7 synthetic prostanoid analogues.2 Sulprostone (EPI EP3) and 16,16-dimethyl PGE2 (EPI = EP2 = EP3) were as potent as PGE2 in inducing allodynia, and more potent than sulprostone. Butaprost (EP2), 1 1-deoxy PGE, (EP2 = EP3), MB 28767 (EP3), and cicaprost (prostaglandin 12 (IP-) receptor) induced allodynia, but with much lower scores. 13,14-Dihydro-I5-keto PGE2, a metabolite of PGE2, did not induce allodynia. 4 16,16-Dimethyl PGE2 as well as PGE2 induced hyperalgesia over a wide range of dosages (16,16-dimethyl PGE2: 5 pg-0.5 pg kg-' PGE2: 50 pg-0.5 gg kg-') with two apparent peaks at 0.5 ng kg-' and 0.5 gg kg-'. Sulprostone (EPI EP3) showed a bell-shaped hyperalgesia at lower doses of Spg-Sngkg'1 and 50pg-50ngkg-', respectively. MB28767 (EP3) showed a monophasic hyperalgesic action over a wide range of dosages at 50 pg-S5 jg kg-'. Butaprost (EP2) induced hyperalgesia at doses higher than 50ngkg-'. 5 These results demonstrate that PGE2 may exert allodynia through the EP,-receptor and hyperalgesia through EP2-and EP3-receptors in the mouse spinal cord.

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Muscle relaxation appears to facilitate ProSeal insertion efficacy by enabling higher successful insertion rates, higher sealing pressure, lower leakage volume, and lower subjective difficulty of insertion in anesthetized patients.

In order to investigate the involvement of glutamate receptor systems in allodynia induced by prostaglandin (PG) E2 or F2 alpha, we co-administered antagonists for N-methyl-D-aspartate (NMDA), non-NMDA, or metabotropic glutamate receptors intrathecally with PGE2 or PGF2 alpha and examined their effects on the allodynia evoked in conscious mice by non-noxious brushing of the flanks. MK-801, a non-competitive NMDA receptor channel blocker, and D-AP-5, a selective NMDA receptor antagonist, dose-dependently blocked PGE2-induced allodynia with an IC50 of 1.60 and 0.52 microgram/mouse, respectively. A glycine binding-site antagonist for the NMDA receptor, 7-Cl-KYNA, did not influence it. None of these NMDA receptor antagonists inhibited PGF2 alpha-evoked allodynia. Non-NMDA receptor antagonists GAMS and CNQX inhibited both PGE2- and PGF2 alpha-induced allodynia. On the other hand, L-AP-3 and L-AP-4, putative metabotropic glutamate receptor antagonists, dose-dependently antagonized the allodynia induced by PGF2 alpha with an IC50 of 0.92 and 3.26 ng/mouse, respectively, but not that induced by PGE2. Intrathecal administration of L-glutamate produced allodynia over a wide range of low doses from 0.1 pg to 0.1 microgram/mouse, and the maximal effect was observed at 1 ng. Similar to allodynia induced by prostaglandins, the response lasted over a 50-min experimental period. These results demonstrate that both PGE2- and PGF2 alpha-evoked allodynia are mediated through a pathway that includes the glutamate receptor system but that subtypes of glutamate receptors involved and sites of action in the spinal cord may be different between them.

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We recently reported that intrathecal (i.t.) administration of prostaglandin (PG) E2 or PGF2 alpha in conscious mice induced allodynia through a pathway that includes the glutamate receptor system. Allodynia induced by PGE2 and PGF2 alpha was blocked by antagonists for NMDA and metabotropic glutamate receptor subtypes, respectively. In the present study, we examined the possibility for the involvement of nitric oxide (NO) in the PG-evoked allodynia. Allodynia was assessed once every 5 min by light stroking of the flank of mice with a paintbrush. Intrathecal administration of L-arginine, a substrate of nitric oxide synthase (NOS), in conscious mice resulted in allodynia. Dose dependency of L-arginine for allodynia showed a bell-shaped pattern (1-10 micrograms/mouse). The maximal allodynic effect was observed with 5.0 micrograms at 10-15 min after i.t. injection, similar in time course and magnitude to that induced by L-glutamate. L-Arginine-induced allodynia was dose-dependently reduced by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue with IC50 values of 7.68 and 8.70 pg/mouse, respectively. PGE2-induced allodynia was also dose-dependently inhibited by L-NAME and methylene blue with IC50 values of 94.7 and 74.9 pg/mouse. PGF2 alpha-induced allodynia was inhibited by methylene blue with an IC50 value of 40.6 pg/mouse, but not by L-NAME at doses up to 1.0 ng.(ABSTRACT TRUNCATED AT 250 WORDS)

These results demonstrate that both strychnine- and bicuculline-evoked allodynia were mediated through pathways that include the glutamate receptor and nitric oxide systems but in a different manner. the current study suggests that GABA and glycine may modulate responses to an innocuous tactile stimulus as inhibitory neurotransmitters at presynaptic and postsynaptic sites in the spinal cord, respectively.

1 We recently demonstrated that intrathecal administration of prostaglandin E 2 (PGE 2 ) and PGF 2a induced allodynia through a pathway that includes the glutamate receptor and nitric oxide (NO)-generating systems from pharmacological studies. In order to clarify the involvement of NO in prostaglandin-induced allodynia, we measured NO released from rat spinal cord slices by a chemiluminescence method. 2 PGE 2 stimulated NO release from both dorsal and ventral regions all along the spinal cord. PGE 2 stimulated the release within 10 min and increased it in a time-dependent manner. 3 The PGE 2 -induced NO release was observed at 100 nM ± 10 mM. PGF 2a stimulated the release at concentrations higher than 1 mM, but PGD 2 (up to 10 mM) did not enhance it. 4 17-Phenyl-o-trinor PGE 2 (EP 1 4EP 3 ) and sulprostone (EP 1 5EP 3 ) were as potent as PGE 2 , but PGE 1 was less potent, in stimulating NO release. While M&B 28767 (EP 3 ) did not enhance the release, butaprost (EP 2 ) stimulated it at 1 mM. The PGE 2 -evoked release was blocked by ONO-NT-012, a bifunctional EP 1 antagonist/EP 3 agonist. 5 The PGE 2 -evoked release was Ca 2+ -dependent and blocked by MK-801 (NMDA receptor antagonist) and L-NAME (NO synthase inhibitor). The release was also inhibited by PGD 2 and dibutyryl-cyclic AMP. 6 The present study demonstrated that PGE 2 stimulates NO release in the rat spinal cord by activation of NMDA receptors through the EP 1 receptor, and supports our previous ®ndings that the NOgenerating system is involved in the PGE 2 -induced allodynia.