1.
Agmatine, the proposed endogenous
ligand for
imidazoline receptors, has been shown to attenuate tolerance to
morphine-induced antinociception (Kolesnikov el al., 1996). The main aim of this study was to assess if
idazoxan, an alpha2-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-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. 3. The concurrent chronic administration (10 mg kg(-1), i.p., 13 days) of
2-BFI,
LSL 60101, and
LSL 61122 (
valldemossine), selective and potent I2-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 I2-imidazoline receptors in the modulation of
opioid tolerance. 4. 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 alpha2-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 alpha2-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 alpha2-adrenoceptors and I(1)-imidazoline receptors in the modulatory effect of
idazoxan on
opioid tolerance. 5.
Idazoxan and other imidazol(ine) drugs fully inhibited [3H]-(+)-
MK-801 binding to
N-methyl-D-aspartate (
NMDA) receptors in the rat cerebral cortex with low potencies (Ki: 37-190 microM). 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(-1), i.p.) was associated with a marked decrease (49%) in immunolabelled
neurofilament 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(-1)) and
LSL 60101 (10 mg kg(-1)) 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 I2-imidazoline
ligands attenuates the development of tolerance to
opiate drugs and may induce
neuroprotective effects on chronic
opiate treatment. Moreover, these findings offer the I2-imidazoline
ligands as promising therapeutic coadjuvants in the management of chronic
pain with
opiate drugs.