The involvement of noradrenergic transmission in the morphine‐induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment

Abstract

1 Our previous studies suggest that in addition to the cerebral dopaminergic systems the noradrenergic ones have a crucial role in the morphine-induced behavioural sensitization in mice. Therefore the e ects of a 2 -adrenoceptor antagonist, idazoxan (1 and 3 mg kg 71 , i.p.) on morphineinduced locomotor hyperactivity as well as on morphine-induced changes in cerebral noradrenaline (NA) and striatal dopamine (DA) metabolism were studied in mice withdrawn for 3 days from 5 day repeated morphine treatment. The concentrations of NA, free 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine (3-MT) were determined. 2 Acute morphine (10 mg kg 71 , s.c.) increased locomotor activity in control and in morphinewithdrawn mice; idazoxan alone did not alter the activity. Idazoxan pretreatment did not alter the locomotor hyperactivity induced by acute morphine in control mice but potentiated it in morphinewithdrawn mice. 3 Acute morphine elevated MOPEG less but increased DOPAC and HVA more clearly in morphine-withdrawn mice than in controls, and decreased 3-MT only in controls. Idazoxan alone did not alter the NA or DA metabolite concentrations in control mice, but elevated MOPEG as well as DOPAC in morphine-withdrawn mice. 4 In control mice idazoxan enhanced acute morphine's elevating e ect on MOPEG. In withdrawn mice idazoxan counteracted the tolerance so that acute morphine elevated MOPEG in these mice to about similar level as in controls. 5 Idazoxan pretreatment abolished the HVA increasing e ect of acute morphine both in control and withdrawn mice. In control mice idazoxan enhanced morphine's elevating e ect on DOPAC and abolished morphine's decreasing e ect on 3-MT. Idazoxan did not alter morphine's e ects on DOPAC or 3-MT concentrations in withdrawn mice. 6 Our results show that in morphine-withdrawn mice idazoxan pretreatment reveals the morphineinduced locomotor sensitization. This most probably occurs by overcoming the tolerance towards the acute morphine-induced increase of cerebral NA turnover and release. It is suggested that in mice the cerebral noradrenergic in addition to the dopaminergic systems are major determinants of the behavioural sensitization to morphine.

Biological significance of agmatine, an endogenous ligand at imidazoline binding sites

“…How this binding site mediates suppression of the development of tolerance is still not completely understood, even considering the fact that I 2 ‐binding sites have been implicated as a regulatory binding site on MAO. Moreover, results using idazoxan, showing increases in cerebral levels of 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MOPEG) and 3,4,dihydroxy‐phenylacetic acid (DOPAC) in morphine‐withdrawn mice and an enhancement of morphine's elevating effects on MAO ( Airio & Ahtee, 1999 ) suggests rather an interaction with MAO than an increase in cerebral noradrenaline turnover and release as a mechanism underlying idazoxan's overcoming of morphine tolerance. However, such a noradrenaline release can not be mediated classically via presynaptic α 2 ‐adrenoceptor, since it has repeatedly been shown that idazoxan inhibits noradrenaline release by this mechanism ( Molderings et al ., 1997 ).…”

Opiate withdrawal in the neonatal rat: relationship to duration of treatment and naloxone dose

“…A large literature in adults supports a role for the involvement of norepinephrine in opiate withdrawal (Nader and van der Kooy 1996;Airio and Ahtee 1999), although the role of alpha 2 adrenergic receptors in suppressing withdrawal is clearer than the role of locus coeruleus activation in producing withdrawal behaviors (Caille et al 1999). Evidence supporting both mechanisms has been shown in neonatal rats.…”

Benefit of tianeptine and morphine in a transgenic model of familial amyotrophic lateral sclerosis

“…Opiates generally exert their effects through increased dopaminergic transmission in the mesolimbic system (35), even if this is controversial (36). Morphine-induced hyperactivity is related to supersensitivity of post-synaptic dopaminergic receptors, but GABAergic, glutamatergic and noradrenergic systems also play a critical role (37)(38)(39)(40). In our study, wheel activity was quantified a few hours after drug injection.…”