Attenuation of tolerance to opioid‐induced antinociception and protection against morphine‐induced decrease of neurofilament proteins by idazoxan and other I₂‐imidazoline ligands

Abstract

1 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 a 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. 2 Antinociceptive responses to opioid drugs were determined by the tail-¯ick test. The acute administration of morphine (10 mg kg 71 , i.p., 30 min) or pentazocine (10 mg kg 71 , i.p., 30 min) resulted in marked increases in tail-¯ick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg 71 , 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. 3 The concurrent chronic administration (10 mg kg 71 , 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 71 , 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 morphineinduced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the speci®c involvement of I 2 -imidazoline receptors in the modulation of opioid tolerance. The potencies of the imidazolines idazoxan, RX821002 and moxonidine were similar, indicating a lack of relationship between potency on NMDA receptors and ability to attenuate opioid tolerance. These results suggested that modulation of opioid tolerance by idazoxan is not related to NMDA receptors blockade. 6 Chronic treatment (13 days) with morphine (10 mg kg 71 , i.p.) was associated with a marked decrease (49%) in immunolabelled neuro®lament proteins (NF-L) in the frontal cortex of morphine-tolerant rats, suggesting the induction of neuronal damage. Chronic treatment (13 days) with idazoxan (10 mg kg 71 ) and LSL 60101 (10 mg kg 71 ) did not modify the levels of NF-L proteins in brain. Interestingly, the concurrent chronic treatment (13 days) of idazoxan or LSL 60101 and morphine, completely reversed the morphine-induced decrease in NF-L immunoreactivity, suggesting a neuroprotective role for these drugs. 7 Together, the results indicate that chronic treatment with I 2 -imidazoline ligands attenuates the development of tolerance to opiate drugs and may induce neuroprotective eects on chronic opiate treatment. Moreover, these ®ndings oer the I 2 -imidazoline ligands as promising therapeutic coadjuvants in the management of chronic pain with opiate drugs.

Regulation of nonphosphorylated and phosphorylated forms of neurofilament proteins in the prefrontal cortex of human opioid addicts

“…This study also demonstrated that the opioid modulation of NF-L proteins also occurs in the prefrontal cortex, a brain region that is also a target for the chronic effects of opioid drugs in humans (Escribá et al, 1994;Busquets et al, 1995;Simonato, 1996). Recently, chronic treatment of rats with morphine also induced a marked decrease (49%) in NF-L immunoreactivity in the frontal cortex (Boronat et al, 1998).…”

“…Acute morphine treatment in rats has been shown not to alter the density of nonphosphorylated NF proteins in the VTA (Beitner-Johnson et al, 1992) or to modestly increase their abundance in the frontal cortex (unpublished experiments). In contrast, chronic morphine treatment was associated with marked decreases in nonphosphorylated NF-L (49%) (Boronat et al, 1998) and NF-H (38%) (unpublished experiments) in the rat frontal cortex. It, therefore, appears that the decreases in total immunodensity of NF proteins in brains of opioid addicts are the result of a chronic opioid effect.…”

“…The mechanism by which morphine alters the size and dendritic structure of neurones is not known, but it may be related to the ability of opiate drugs to alter NF proteins (Beitner-Johnson et al, 1992;García-Sevilla et al, 1997a;Boronat et al, 1998;present results). Therefore, it has been suggested that these structural and functional changes may reflect neural injury induced by chronic opioid exposure in rats (Nestler, 1996) and in humans (García-Sevilla et al, 1997a;present results).…”

RX 821002 as a Tool for Physiological Investigation of α2‐Adrenoceptors

“…Subsequent development of the idazoxan molecule showed that bulky substitutions at the 2-position of the benzodioxanyl ring gave improved potency and selectivity at the á 2 -receptor. Two molecules showed particularly good characteristics: 2-ethoxy-idazoxan (2-(2-ethoxy-2,3-dihydrobenzo [1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole, RX 811059) and 2-methoxy-idazoxan (RX 821002, 2-(2-methoxy-2,3-dihydro-benzo [1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole, Fig. 1) gave improved potency at á 2 -adrenoceptors and á 2 /á 1 selectivity ratios of > 100 (103,114).…”

Twin and Triplet Drugs in Opioid Research

“…IBS ligands were reported to modulate antinociception [121,122], tolerance [123][124][125], and dependence [126][127][128] induced by opioids. In a preliminary study [129], fentanyl (58) and the guanidine moiety, which mimics an endogenous I 2 -IBS ligand agmatine (59) [130], were chosen as the opioid and I 2 -IBS pharmacophores, respectively, to provide twin drugs 61 and 62.…”