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We investigated the effects of aging on forced walking stress-induced analgesia using a formalin-induced paw licking test in male mice. Exposure to forced walking stress for 6 h showed forced walking stress-induced analgesia in all mice aged 4, 24 and 48 weeks in the second phase (10-30 min), but not in the first phase (0-10 min). In the second phase, the degree of stress-induced analgesia was age-dependent (4 > 24 > 48 weeks). LY-235959, a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, blocked forced walking stress-induced analgesia in mice aged 4 and 24 weeks, but not in those aged 48 weeks. Naloxone did not antagonize forced walking stress-induced analgesia in mice in any of the age groups. The present study suggests that the degree of forced walking stress-induced analgesia depends on the age of mice and confirms previous findings that forced walking stress-induced analgesia is involved in the nonopioid system via NMDA receptors.

The authors investigated the effects of spinal and supraspinal administration of the benzodiazepine receptor agonist midazolam alone and with opioids on tests of nociception (tail-flick and hot-plate tests) and motor function (catalepsy) in rats. At the spinal level, the dose-response curves for peak effect and area under the curve for morphine were shifted to the left (indicating potentiation) by a submaximal dose of intrathecal (i.t.) midazolam (20 micrograms) in both nociceptive tests. Additionally, 2.5 micrograms of i.t. midazolam, a dose having no effect when given alone, increased antinociception in both tests when given with i.t. morphine. Isobolographic analysis confirmed that i.t. injection of midazolam potentiated antinociception induced by i.t. morphine. At the supraspinal level, intracerebroventricular (i.c.v.) injection of 4 micrograms of midazolam inhibited morphine antinociception, i.e., the dose-response curve for morphine in the hot-plate test shifted to the right. Midazolam did not affect morphine antinociception in the tail-flick test. Catalepsy occurred only when the highest doses of i.t. or i.c.v. morphine or midazolam were injected alone. The differing effect of midazolam on morphine-induced antinociception suggests that different mechanisms are involved in the spinal cord and brain.

The mechanisms for the combined antinociceptive effect of midazolam and morphine administered at spinal (intrathecal, i.t.) and supraspinal (intracerebroventricular, i.c.v.) levels were investigated in rats. Nociceptive test results showed that co-administration of midazolam and morphine at the spinal level potentiated morphine-induced antinociception, and that this interaction was blocked by intraperitoneal (i.p.) naloxone and reversed by i.t. bicuculline and i.p. flumazenil. Also, bicuculline and flumazenil blocked midazolam-induced antinociception at the spinal level, and naloxone completely reversed morphine antinociception. In contrast, when drugs were injected intracerebroventricularly, midazolam inhibited the antinociceptive effect of morphine (as determined by the hot-plate test). The inhibitory effects of i.c.v. midazolam upon i.c.v. morphine antinociception were partly blocked by flumazenil and bicuculline. Midazolam-induced antinociception was increased by bicuculline and decreased by flumazenil; naloxone i.p. blocked both i.c.v. morphine antinociception and i.c.v. morphine-midazolam antinociception. Results after i.t. injection may be due to an interaction between morphine and midazolam/GABAA receptor-activated systems. At the supraspinal level, this interaction may also activate other systems that are distinct from those governing the individual action of each agonist.

Background and study aims: No prospective comparison of endoscopic ultrasonography-guided direct celiac ganglia neurolysis (EUS-CGN) vs. EUS-guided celiac plexus neurolysis (EUS-CPN) has been reported. The aim of the current study was to compare the effectiveness of EUS-CGN and EUS-CPN in providing pain relief from upper abdominal cancer pain in a multicenter randomized controlled trial. Patients and methods: Patients with upper abdominal cancer pain were randomly assigned to treatment using either EUS-CGN or EUS-CPN. Evaluationwas performed at Day 7 postoperatively using a pain scale of 0 to 10.Patients for whom pain decreased to⩽3 were considered to have a positive response, and those experiencing a decrease in pain to⩽1 were considered to be completely responsive. Comparison between the two groups was performed using intention-to-treat analysis. The primary endpoint was the difference in treatment response rates between EUS-CGN and EUS-CPN at postoperative Day 7.Secondary endpoints included differences in complete response rates, pain scores, duration of pain relief, and incidence of adverse effects. Results: A total of 34 patients were assigned to each group. Visualization of ganglia was possible in 30 cases (88 %) in the EUS-CGN group.The positive response ratewas significantly higher in the EUS-CGN group (73.5 %) than in the EUS-CPN group (45.5 %; P=0.026). The complete response rate was also significantly higher in the EUS- CGN group (50.0 %) than in the EUS-CPN group (18.2 %; P=0.010). There was no difference in adverse events or duration of pain relief between the two groups. Conclusions: EUS-CGN is significantly superior to conventional EUS-CPN in cancer pain relief. [ABSTRACT FROM AUTHOR]