Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 130 (1), 146-52

Activation of I(2)-imidazoline Receptors Enhances Supraspinal Morphine Analgesia in Mice: A Model to Detect Agonist and Antagonist Activities at These Receptors

Affiliations

Activation of I(2)-imidazoline Receptors Enhances Supraspinal Morphine Analgesia in Mice: A Model to Detect Agonist and Antagonist Activities at These Receptors

P Sánchez-Blázquez et al. Br J Pharmacol.

Abstract

This work investigates the receptor acted upon by imidazoline compounds in the modulation of morphine analgesia. The effects of highly selective imidazoline ligands on the supraspinal antinociception induced by morphine in mice were determined. 2. Intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of ligands selective for the I(2)-imidazoline receptor, 2-BFI, LSL 60101, LSL 61122 and aganodine, and the non selective ligand agmatine, increased morphine antinociception in a dose-dependent manner. Neither moxonidine, a mixed I(1)-imidazoline and alpha(2)-adrenoceptor agonist, RX821002, a potent alpha(2)-adrenoceptor antagonist that displays low affinity at I(2)-imidazoline receptors, nor the selective non-imidazoline alpha(2)-adrenoceptor antagonist RS-15385-197, modified the analgesic responses to morphine. 3. Administration of pertussis toxin (0.25 microg per mouse, i.c.v.) 6 days before the analgesic test blocked the ability of the I(2)-imidazoline ligands to potentiate morphine antinociception. 4. The increased effect of morphine induced by I(2)-imidazoline ligands (agonists) was completely reversed by idazoxan and BU 224. Identical results were obtained with IBI, which alkylates I(2)-imidazoline binding sites. Thus, both agonist and antagonist properties of imidazoline ligands at the I(2)-imidazoline receptors were observed. 5. Pre-treatment (30 min) with deprenyl, an irreversible inhibitor of monoamine oxidase B (IMAO-B), produced an increase of morphine antinociception. Clorgyline, an irreversible IMAO-A, given 30 min before morphine did not alter the effect of the opioid. At longer intervals (24 h) a single dose of either clorgyline or deprenyl reduced the density of I(2)-imidazoline receptors and prevented the I(2)-mediated potentiation of morphine analgesia. 6. These results demonstrate functional interaction between I(2)-imidazoline and opioid receptors. The involvement of G(i)-G(o) transducer proteins in this modulatory effect is also suggested.

Figures

Figure 1
Figure 1
Effect of I2-imidazoline ligands on the supraspinal antinociceptive effect induced by morphine in the 52°C hot water tail-flick test. Mice were injected with a fixed dose of imidazolines (10 μg per mouse) 30 min before morphine and the antinociceptive activity was evaluated by the tail-flick test. All compounds were i.c.v. injected in volumes of 4 μl. For each treatment a different group of animals were used. Latencies were measured before and 30 min after administration of morphine. Antinociception is expressed as a percentage of the maximum possible effect (MPE). Values are means±s.e.mean from groups of 10–20 mice each. *Significantly different from the control group receiving saline. Analysis of variance, Student-Newman-Keuls test, P<0.05.
Figure 2
Figure 2
Effect of 2-BFI and LSL61122 on morphine antinociception (A) the effect of increased doses of 2-BFI and LSL61122 were tested upon the antinociceptive response to a fixed dose of morphine (1 μg per mouse, i.c.v.). Imidazoline compounds were given 30 min before morphine administration. The data indicate the percentage of increase respect to the antinociceptive effect induced by morphine alone (35.6±2.8% MPE). (B) Dose-response curves for morphine antinociception in mice were constructed in the absence and presence of 2-BFI (10 μg per mouse). Antinociception was evaluated in the 52°C hot-water tail-flick test and is expressed as a percentage of the maximum possible effect (MPE). All values are means±s.e.mean from groups of 10–15 mice. *Significantly different from the control group receiving saline instead of imidazoline. Analysis of variance, Student-Newman-Keuls test, P<0.05.
Figure 3
Figure 3
Blockade by IBI of the potentiation of morphine analgesia induced by I2-imidazoline agonists. The alkylating ligand for the I2-imidazoline receptors, IBI (40 μg per mouse, i.c.v.), was injected 24 h before the antinociceptive test. Imidazoline compounds (10 μg per mouse) were given 30 min before morphine administration. Latencies were measured 30 min after morphine. For each treatment a different group of animals was used. Antinociception was evaluated in the 52°C hot-water tail-flick test and is expressed as a percentage of the maximum possible effect (MPE). Values are means±s.e.mean from groups of 10–15 mice each. *Significantly different from the control group receiving saline; **from the corresponding group not receiving IBI. Analysis of variance, Student-Newman-Keuls test, P<0.05.
Figure 4
Figure 4
Effect of pertussis toxin on the potentiation of morphine analgesia induced by the putative I2-imidazoline agonists. The toxin (0.25 μg per mouse, i.c.v.) was injected 6 days before the analgesic test (see Methods). Imidazoline compounds (10 μg per mouse) were given 30 min before morphine administration and latencies were measured 30 min after administration of morphine. For each treatment a different group of animals was used. Antinociception was evaluated in the 52°C hot-water tail-flick test and is expressed as a percentage of the maximum possible effect (MPE). Values are the means±s.e.mean from groups of 10–12 mice each. *Significantly different from the group treated with pertussis toxin and receiving saline. Analysis of variance, Student-Newman-Keuls test, P<0.05.

Similar articles

See all similar articles

Cited by 28 PubMed Central articles

See all "Cited by" articles

Publication types

LinkOut - more resources

Feedback