J Neurosci. 2002 Sep 1;22(17):7650-61.
Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism.
Mao J, Sung B, Ji RR, Lim G.
Massachusetts General Hospital Pain Center, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
[email protected]
Tolerance to the analgesic effect of an opioid is a pharmacological phenomenon that occurs after its prolonged administration. Activation of the NMDA receptor (NMDAR) has been implicated in the cellular mechanisms of opioid tolerance. However, activation of NMDARs can lead to neurotoxicity under many circumstances. Here we demonstrate that spinal neuronal apoptosis was induced in rats made tolerant to morphine administered through intrathecal boluses or continuous infusion. The apoptotic cells were predominantly located in the superficial spinal cord dorsal horn, and most apoptotic cells also expressed glutamic acid decarboxylase, a key enzyme for the synthesis of the inhibitory neurotransmitter GABA. Consistently, increased nociceptive sensitivity to heat stimulation was observed in these same rats. Mechanistically, the spinal glutamatergic activity modulated morphine-induced neuronal apoptosis, because pharmacological perturbation of the spinal glutamate transporter activity or coadministration of morphine with the NMDAR antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate affected both morphine tolerance and neuronal apoptosis. At the intracellular level, prolonged morphine administration resulted in an upregulation of the proapoptotic caspase-3 and Bax proteins but a downregulation of the antiapoptotic Bcl-2 protein in the spinal cord dorsal horn. Furthermore, coadministration with morphine of N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (a pan-caspase inhibitor) or acetyl-aspartyl-glutamyl-valyl-aspart-1-aldehyde (a relatively selective caspase-3 inhibitor) blocked morphine-induced neuronal apoptosis. Blockade of the spinal caspase-like activity also partially prevented morphine tolerance and the associated increase in nociceptive sensitivity. These results indicate an opioid-induced neurotoxic consequence regulated by the NMDAR-caspase pathway, a mechanism that may have clinical implications in opioid therapy and substance abuse.
Neural activity associated with cognitive regulation in heroin users: A fMRI study.
Lee TM, Zhou WH, Luo XJ, Yuen KS, Ruan XZ, Weng XC.
Neuropsychology Laboratory, The University of Hong Kong, Hong Kong, PR China.
Previous research has found heroin addicts to be impulsive. This study employed functional magnetic resonance imaging technology to investigate the differences between heroin addicts and normal controls in neural activity associated with cognitive regulation of behavior. Twenty-one Chinese men participated in this study, 11 of whom were newly admitted heroin-addicted patients and 10 of whom were healthy volunteers. In the experimental task, the subjects were required to first identify the correct directions of arrowheads and then give the opposite answers. Behaviorally, the heroin-dependent patients took a much shorter time to complete the more demanding second part of the task but committed more errors than the normal controls. This pattern of behavior, characteristic of people who are disinhibited and who tend to be impulsive, was consistent with previous reports of impulsivity observed in people who have abused heroin. The neural activity of the patients that was associated with performing the experimental task of cognitive regulation was different to that of the normal controls in terms of the pattern of prefrontal activation, the attenuation of activity in the anterior cingulate, and the additional recruitment of the right inferior parietal region. This study is the first that seeks to understand the neural activity associated with impulsive behavior in people who abuse heroin. The pattern of imaging data obtained resembled the pattern of data observed in immature brains attempting to exercise cognitive control of behavior. Further theoretical and clinical implications of the findings are discussed.
Heroin abusers' performance on the Tower of London Test relates to the baseline EEG alpha2 mean frequency shifts.
Davydov DM, Polunina AG.
Department of Neuropsychology, Moscow Research Practical Center for Prevention of Drug Addiction, 156-368 Leninsky pr-t, Moscow 117571, Russia.
Planning function deficit is the most consistent finding in neuropsychological studies of heroin addicts. The performance on the Tower of London Test (TLT) correlated with the duration of daily heroin abuse (DDHA) in our previous study. Alpha2 mean frequency in anterior/central derivations was also predicted by DDHA in the same patient population. This retrospective study was undertaken in order to understand better the relationships between observed neurological deviations in heroin abusers. Thirty-three heroin addicts and 12 healthy males were evaluated with 14 neuropsychological tests and resting eyes-closed electroencephalography (EEG). Multivariate tests showed that performance on the difficult (five-move) problems of TLT was strongly predicted by the EEG alpha2 mean frequency shifts, and these relationships were generally mediated by chronic heroin length. However, post-hoc analyses at separate leads demonstrated that the relationships between cognitive variables and alpha2 mean frequencies in the left hemisphere were independent of chronic heroin effects, whereas elevation of alpha2 frequency in the right hemisphere was strongly predicted by chronic heroin intake length. The patients with extremely high alpha2 mean frequency at the left central region were especially prone to failure in TLT due to the inability of the hypothesized alpha2-generating network, which normally projects to the central and temporal derivations bilaterally and to the right posterior temporal derivation to function appropriately. Hence, it was concluded that planning dysfunction in heroin abusers is related to alpha2 mean frequency shifts predominantly at the central regions.
Prog Neuropsychopharmacol Biol Psychiatry. 2004 Nov;28(7):1109-15.
Long-term abstinence syndrome in heroin addicts: indices of P300 alterations associated with a short memory task.
Papageorgiou CC, Liappas IA, Ventouras EM, Nikolaou CC, Kitsonas EN, Uzunoglu NK, Rabavilas AD.
Psychophysiology Laboratory, Department of Psychiatry, Eginition Hospital, University of Athens Medical School, 74 Vas. Sophias Avenue, Athens, 11528, Greece.
[email protected]
Attentional deficits have been implicated in the pathophysiology of opioid addicts. The P300 component of event-related potentials (ERPs) is considered as a manifestation of attentional operations. The authors' goal was the comparison of P300 elicited during a short memory test between subjects with prolonged heroin abstinence and current heroin users as well as healthy controls. The P300 component was evaluated during the anticipatory period of a short memory task in 20 patients characterized by a past history of opioid dependence (6 months abstinence), in 18 current heroin users and in 20 healthy comparison subjects, matched for age, sex and educational level. Abstinent heroin addicts exhibited significant reduction of P300 amplitude at central frontal region, relative to the other two groups. The findings are discussed in connection to the aim of identifying psychophysiological indices, addressing issues in opioid use disorders, and suggest that knowledge about cognitive operations, such as those reflected by P300 component, could provide further insight into psychophysiological mechanisms underlying the long-term abstinence state of heroin addicts.
Neuropsychopharmacology. 2000 Aug;23(2):113-26.
Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers.
Ornstein TJ, Iddon JL, Baldacchino AM, Sahakian BJ, London M, Everitt BJ, Robbins TW.
Department of Psychiatry, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, UK.
Groups of subjects whose primary drug of abuse was amphetamine or heroin were compared, together with age- and IQ-matched control subjects. The study consisted of a neuropsychological test battery which included both conventional tests and also computerised tests of recognition memory, spatial working memory, planning, sequence generation, visual discrimination learning, and attentional set-shifting. Many of these tests have previously been shown to be sensitive to cortical damage (including selective lesions of the temporal or frontal lobes) and to cognitive deficits in dementia, basal ganglia disease, and neuropsychiatric disorder. Qualitative differences, as well as some commonalities, were found in the profile of cognitive impairment between the two groups. The chronic amphetamine abusers were significantly impaired in performance on the extra-dimensional shift task (a core component of the Wisconsin Card Sort Test) whereas in contrast, the heroin abusers were impaired in learning the normally easier intra-dimensional shift component. Both groups were impaired in some of tests of spatial working memory. However, the amphetamine group, unlike the heroin group, were not deficient in an index of strategic performance on this test. The heroin group failed to show significant improvement between two blocks of a sequence generation task after training and additionally exhibited more perseverative behavior on this task. The two groups were profoundly, but equivalently impaired on a test of pattern recognition memory sensitive to temporal lobe dysfunction. These results indicate that chronic drug use may lead to distinct patterns of cognitive impairment that may be associated with dysfunction of different components of cortico-striatal circuitry.
Physiological and psychological effects of methadone in man.
Gritz ER, Shiffman SM, Jarvik ME, Haber J, Dymond AM, Coger R, Charuvastra V, Schlesinger J.
Methadone hydrochloride-maintenance outpatients were compared to abstinent exaddicts on physiological and psychological measures, and to normal subjects on physiological measures. The battery of psychological tests measure cognitive abilities and mental state. Methadone depressed respiration rate below other groups; abstinent subjects had higher heart rates than methadone or control subjects. No other physiological differences appeared. Electroencephalographic spectral analysis disclosed that the location of the alpha peak was at the lowest frequency in the methadone group, next lowest being the abstinent group. Discriminant functions based on a weighted combination of variables (frequencies) successfully distinguished the EEGs of the three groups. Both discriminant analysis and multiple regression analysis indicated that EEG changes were dose-dependent. Methadone subjects performed significantly poorer on several tests of learning and immediate recall compared to absitinent subjects.
Neuropsychobiology. 2002;45(2):67-73. Related Articles, Links
Opioid addiction changes cerebral blood flow symmetry.
Pezawas L, Fischer G, Podreka I, Schindler S, Brucke T, Jagsch R, Thurnher M, Kasper S.
Department of General Psychiatry, University of Vienna, Austria. Lukas.Peza
Changes in regional cerebral blood flow (rCBF) due to long-term abuse of opioids such as heroin or morphine are not yet fully understood in humans. The goal of the present study was to investigate rCBF alterations in a large sample of long-term opioid addicts in comparison to healthy controls. We investigated 21 opioid-dependent subjects, who were currently abusing heroin or were enrolled in a methadone or morphine maintenance program, and 36 healthy controls with (99m)Tc-HMPAO single photon emission computed tomography. We found a decrease in rCBF in most regions of interest in patients in comparison to controls. Long-term opioid dependence seems to decrease prefrontal CBF in particular. A right-greater-than-left CBF asymmetry in healthy subjects was reversed in patients. This change in CBF symmetry could reflect the different emotional status of opioid-dependent patients. Our findings are in line with neuropsychological investigations indicating a correlation of mood states with lateralization of hemispheric activation patterns. Copyright 2002 S. Karger AG, Basel
In summary, there is evidence the points to possible nuerotoxicity of opiods as well.
