Dissociation of analgesic and rewarding effects of endomorphin-1 in rats.

The mu-receptor is the primary mediator of the effects of morphine and the endogenous opiates, endomorphin-1 and endomorphin-2. Here we demonstrate a dissociation of the analgesic and rewarding effects of endomorphin-1 in rats. Tail-flick results revealed that endomorphin-1 produced significant analgesic effects within 10-min after injection. However, it failed to show reward properties in the standard 45- min conditioned place preference (CPP) paradigm or in an abbreviated 10-min pairing which paralleled the time frame of the tail-flick findings. Morphine induced both analgesia and reward. Endomorphin-1 therefore is the first mu opiate shown to produce potent analgesia in the absence of reward behavior, and thus may have significant clinical potential.

The role of corticosterone in the blockade of tolerance to morphine analgesia by formalin-induced pain in the rat.

We previously reported that morphine fails to produce analgesic tolerance when administered in the presence of formalin-induced pain, which may be related to activity of the hypothalamic-pituitary-adrenal axis. In the present study, we examined whether suppression of corticosterone secretion during pain prevents the blockade of tolerance to morphine analgesia. Male Long-Evans rats were injected with morphine (20 mg/kg) or saline for 4 consecutive days in the presence or absence of formalin-induced pain. To suppress corticosterone activity, some animals were injected daily with the corticosterone synthesis inhibitor, metyrapone (100 mg/kg), 24 h and 30 min before formalin injections. The analgesic effect of a test dose of morphine (10 mg/kg) was then measured in the tail-flick test 24 h after tolerance induction (i.e. day 5). The presence of pain during tolerance induction prevented the development of analgesic tolerance. Furthermore, inhibition of corticosterone synthesis by metyrapone prevented the blockade of tolerance by pain. These results suggest that the blockade of tolerance to morphine analgesia by formalin-induced pain depends on stress-induced corticosterone increases.

Analgesic effects of endomorphin-1 and endomorphin-2 in the formalin test in mice.

Two recently isolated peptides, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), are highly selective micro-opioid receptor agonists with analgesic actions in the tail-flick test. To further assess the analgesic properties of these peptides, the effects of endomorphin-1, endomorphin-2, and morphine were examined in the formalin test. Male Swiss Webster mice were injected i.c.v. with endomorphin-1, endomorphin-2, or morphine (0, 1, 3, 10 microg) 5 min before injection of 20 microl of 5% formalin s.c. into the plantar surface of one hind-paw. The mice were observed for 60 min after formalin injection. Endomorphin-1 and endomorphin-2 produced dose-dependent analgesia that was shorter in duration than for morphine. Increased locomotion was observed after morphine, but not after endomorphin-1 or endomorphin-2. These findings extend previous results and suggest that endomorphins may have therapeutic potential for the treatment of acute pain.

Reduction of stress-induced analgesia following ethanol exposure in mice.

In the present study, we examined the effects of ethanol treatment on the subsequent expression of opioid and nonopioid forms of swim stress-induced analgesia (SSIA). In Experiment 1, mice were injected with ethanol (2.5 g/kg, i.p.) or an equal volume of saline once a day for two days. Animals received no treatment on day 3. On day 4, the animals were tested for opioid (3-min swim in water maintained at 32 degrees C) or nonopioid (3-min swim in water maintained at 20 degrees C) SSIA in the hotplate test (52 degrees C). Mice pretreated with ethanol injections showed a decrease in nonopioid SSIA, but not in opioid SSIA. In Experiment 2, mice were given an ethanol solution (10%) or tap water to drink for 15 days. On day 16, all animals were given tap water to drink. On day 17, the animals were tested for opioid or nonopioid SSIA. Neither form of SSIA was modified in mice that drank the ethanol solution. These results show that ethanol pretreatment can modify nonopioid endogenous analgesic responses in mice. Further, the route of administration influences the effects of ethanol pretreatment on SSIA.