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Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I 2 ‐imidazoline ligands
Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine‐induced antinociception ( Kolesnikov et al. , 1996 ). The main aim of this study was to assess if idazoxan, an α 2 ‐adrenoceptor antagonist that also interacts with imidazoline recep...
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| Published in: | British journal of pharmacology 2009-02, Vol.125 (1), p.175-185 |
|---|---|
| Main Authors: | , , |
| Format: | Article |
| Language: | English |
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| Online Access: | Get full text |
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| Summary: | Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine‐induced antinociception (
Kolesnikov
et al.
, 1996
). The main aim of this study was to assess if idazoxan, an α
2
‐adrenoceptor antagonist that also interacts with imidazoline receptors, could also modulate opioid tolerance in rats and to establish which type of imidazoline receptors (or other receptors) are involved.
Antinociceptive responses to opioid drugs were determined by the tail‐flick test. The acute administration of morphine (10 mg kg
−1
, i.p., 30 min) or pentazocine (10 mg kg
−1
, i.p., 30 min) resulted in marked increases in tail‐flick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg
−1
, i.p.) was given chronically 30 min before the opiates it completely prevented morphine tolerance and markedly attenuated tolerance to pentazocine (TFLs increased by 71–143% at day 13). Idazoxan alone did not modify TFLs.
The concurrent chronic administration (10 mg kg
−1
, i.p., 13 days) of 2‐BFI, LSL 60101, and LSL 61122 (valldemossine), selective and potent I
2
‐imidazoline receptor ligands, and morphine (10 mg kg
−1
, i.p.), also prevented or attenuated morphine tolerance (TFLs increased by 64–172% at day 13). This attenuation of morphine tolerance was still apparent six days after discontinuation of the chronic treatment with LSL 60101‐morphine. The acute treatment with these drugs did not potentiate morphine‐induced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the specific involvement of I
2
‐imidazoline receptors in the modulation of opioid tolerance.
The concurrent chronic (13 days) administration of RX821002 (10 mg kg
−1
, i.p.) and RS‐15385‐197 (1 mg kg
−1
, i.p.), selective α
2
‐adrenoceptor antagonists, and morphine (10 mg kg
−1
, i.p.), did not attenuate morphine tolerance. Similarly, the concurrent chronic treatment of moxonidine (1 mg kg
−1
, i.p.), a mixed I
1
‐imidazoline receptor and α
2
‐adrenoceptor agonist, and morphine (10 mg kg
−1
, i.p.), did not alter the development of tolerance to the opiate. These results discounted the involvement of α
2
‐adrenoceptors and I
1
‐imidazoline receptors in the modulatory effect of idazoxan on opioid tolerance.
Idazoxan and other imidazol(ine) drugs fully inhibited [
3
H]‐(+)‐MK‐801 binding to N‐methyl‐
D
‐aspartate (NMDA) recepto |
|---|---|
| ISSN: | 0007-1188 1476-5381 |
| DOI: | 10.1038/sj.bjp.0702031 |