Cessation Of Morphine Administration Research Articles

Opioid-induced Loss of Local Anesthetic Potency in the Rat Sciatic Nerve.

Previous evidence suggests that opioid-tolerant patients are less responsive to local anesthetics (LAs) for postoperative pain management. To determine whether this apparent loss of LA potency is due to an intrinsic change in the peripheral nerve, the effect of systemic morphine was assessed on the potency of lidocaine-induced block of the compound action potential in isolated rat sciatic nerves. Analgesic efficacy was assessed with the heat withdrawal assay. While acute administration of 10 mg/kg morphine had no detectable influence on lidocaine potency, seven daily subcutaneous injections of morphine produced a three-fold decrease in potency (EC50 for block A and C waves for naive rats were [mean ± SD] 186 ± 32 μM [n = 6] and 201 ± 31 μM [n = 6], respectively, vs. 608 ± 53 μM [n = 6] and 613 ± 42 μM [n = 6], respectively [P < 0.001], in nerves from rats that had received seven daily injections of morphine [10 mg/kg]). This loss in potency was both dose-dependent and injection number dependent, such that the magnitude of the loss of lidocaine potency was significantly (n = 6; P < 0.01) correlated (r = 0.93) with the development of morphine tolerance. Interestingly, despite the complete recovery of analgesic efficacy within days after cessation of morphine administration, the morphine-induced decrease in lidocaine potency was fully manifest even 35 days after the last morphine injection. Coadministration of naloxone (1 mg/kg, intraperitoneally), but not of naloxone methiodide (1 mg/kg, subcutaneously), with each of seven daily injections of morphine blocked the decrease in lidocaine potency. These preclinical data suggest that the morphine-induced decrease in LA potency is due, at least in part, to the intrinsic changes in the peripheral nerve. Identification of the underlying mechanisms may suggest strategies for more effective postoperative pain management in the growing population of opioid-tolerant patients.

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal.

Vulnerability to stressful life events is a hallmark of drug dependence that may persist long after cessation of drug intake and dramatically fuel key clinical features, such as deregulated up-shifted motivational states and craving. However, to date, no effective therapy is available for reducing vulnerability to stressful events in former drug users and drug-dependent patients, mostly because of poor knowledge of the mechanisms underlying it. In this study, we report that genetic inactivation of the stress-responsive corticotropin-releasing factor receptor-2 (CRF2-/-) completely eliminates the reemergence of increased nonrewarded nose-pokes, reflecting up-shifted motivational states, triggered by ethological environmental stressors long after cessation of morphine administration in mice. Accordingly, CRF2 receptor deficiency completely abolishes the increase in biomarkers of synthesis of major brain motivational substrates, such as ventral tegmental area (VTA) dopamine (DA) and amygdala γ-aminobutyric acid (GABA) systems, associated with the stress-induced reemergence of up-shifted motivational states long after opiate withdrawal. Nevertheless, neither CRF2 receptor deficiency nor long-term opiate withdrawal affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain stress-coping systems. Moreover, CRF2 receptor deficiency does not influence the locomotor or the anxiety-like effect of long-term opiate withdrawal. Thus, the present results reveal an essential and specific role for the CRF2 receptor in the stress-induced reemergence of up-shifted motivational states and related alterations in brain motivational systems long after opiate withdrawal. These findings suggest new strategies for the treatment of the severe and long-lasting vulnerability that inexorably follows drug withdrawal and hinder drug abstinence.

Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys

Clonidine is an alpha2 adrenoceptor agonist that is frequently used to reduce withdrawal symptoms during opioid detoxification in humans. The long-term effects of clonidine on withdrawal symptoms and its effects on subsequent drug exposure have not been thoroughly documented. The aim of the study was to determine if clonidine administered during morphine withdrawal in rhesus monkeys produces long-lasting effects on withdrawal symptoms and alters the effects of subsequently taken drugs of abuse. Adult male rhesus monkeys were treated with increasing doses of morphine for 90 d to induce opiate (narcotic) dependence. The immediate and long-lasting effects of 1 week's administration of clonidine were measured via the recording of morphine withdrawal signs and the subsequent effects of challenge injections of morphine or cocaine. Monkeys chronically treated with morphine displayed withdrawal signs that lasted 2 weeks after cessation of morphine administration and displayed sensitized responses to subsequent morphine and cocaine injections. Clonidine significantly reduced certain morphine withdrawal signs and overall withdrawal score, but these effects did not persist upon cessation of clonidine treatment. Sensitization to the effects of morphine and cocaine were significantly reduced in monkeys previously treated with clonidine. Our results suggest that in addition to its short-term alleviating effect on morphine withdrawal signs, clonidine may reduce subsequent effects of drugs of abuse after prolonged abstinence.

Heme oxygenase type 2 modulates behavioral and molecular changes during chronic exposure to morphine

The heme oxygenase (HO) enzyme system has been shown to participate in nociceptive signaling in a number of different models of pain. In these experiments we investigated the role of the HO type 2 (HO-2) isozyme in tolerance to the analgesic effects of morphine, and the hyperalgesia and allodynia which are measurable upon cessation of administration. Wild type C57Bl/6 wild type mice or HO-2 null mutants in that background strain were treated with morphine for 5 days. The morphine administration protocol consisted of either twice daily repeated s.c. boluses of 15 mg/kg or s.c. implantation of a morphine pellet. At the end of the treatment period wild type mice treated by either protocol exhibited tolerance, but the HO-2 null mutants did not. The HO-2 null mutants also exhibited less mechanical allodynia following cessation of morphine administration, though only modest differences in thermal hyperalgesia were noted. There was no correlation between the degree of tolerance obtained in the bolus and pellet protocols and the degree of hyperalgesia and allodynia observed after cessation of morphine administration in the wild type mice. Our final experiments analyzed increases in expression of mRNA for nitric oxide synthase type 1, N-methyl- d-aspartate (NMDA) receptor NMDAR1 subunit and prodynorphin in spinal cord tissue. In pellet-treated mice two- to three-fold increases were observed in the abundance of these species, but very little change was observed in the null-mutant mice. Taken together our results indicate that HO-2 participates in the acquisition of opioid tolerance, the expression of mechanical allodynia after cessation of opioid administration and in gene regulation occurring in the setting of treatment with morphine. Furthermore, these studies suggest that the mechanisms underlying analgesic tolerance and opioid-induced hypersensitivity are at least somewhat distinct.

Opioid-induced hyperalgesia and incisional pain.

Opioids occupy a position of unsurpassed clinical utility in the treatment of pain of many etiologies. However, recent reports in laboratory animals and humans have documented the occurrence of hyperalgesia when the administration of opioids is abruptly tapered or discontinued, a condition known as opioid-induced hyperalgesia (OIH). In these studies we documented that rats administered morphine (40 mg. kg(-1). day(-1) for 6 days) via subcutaneous osmotic minipumps demonstrated thermal hyperalgesia and mechanical allodynia for several days after the cessation of morphine administration. Additional experiments using a rat model of incisional pain showed that that attributable to OIH were additive with the hyperalgesia and allodynia that resulted from incision. In our final experiments we observed that if naloxone is administered chronically before incision then discontinued (20 mg. kg(-1). day(-1) for 6 days), the hyperalgesia and allodynia that result from hind paw incision was markedly reduced. In contrast, naloxone 1 mg/kg administered acutely after hind paw incision increased hyperalgesia and allodynia. We conclude that the chronic administration of exogenous opioid receptor agonists and antagonists before incision can alter the hyperalgesia and allodynia observed in this pain model, perhaps by altering intrinsic opioidergic systems involved in setting thermal and mechanical nociceptive thresholds. The chronic administration of opioids followed by abrupt cessation can lead to a state of hyperalgesia. In these studies we demonstrate that the hyperalgesia from opioid cessation and from hind paw incision are additive in rats. We suggest that failure to take into consideration preoperative opioid use can lead to excessive postoperative pain.

The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence

The ability of memantine (1-amino-3,5-dimethyladamantane) to block the expression and maintenance of morphine dependence was examined in mice. When administered to morphine-dependent mice 45 min prior to naloxone challenge, memantine (7.5–30 mg/kg IP) in a dose-dependent manner reduced jumping behavior (a manifestation of the expression of dependence). The ability of memantine to attenuate naloxoneprecipitated jumping was reversed by administration of glycine, an observation consistent with electrophysiological studies indicating that memantine is a use-dependent (uncompetitive) N- methyl- d- aspartate (NMDA) antagonist. In an independent series of experiments, the effect of memantine on a preestablished morphine dependence was investigated. A residual dependence to morphine was present 3 days after cessation of morphine administration. Repeated administration of memantine (10 mg/kg, IP) or the competitive NMDA antagonist NPC 17742 [2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid)] (6 mg/kg, IP) during this 3-day period abolished subsequent naloxone-precipitated jumping. In contrast, when administered concurrently with morphine after dependence had already been well established, memantine (10 and 20 mg/kg, IP) did not affect the maintenance of morphine dependence. Based on these findings, NMDA antagonists appear to inhibit the maintenance of opioid dependence, an action distinct from their acute inhibitory effects on the expression of dependence. Nonetheless, these regimen-dependent effects of memantine indicate that the most efficacious use of NMDA antagonists would be in detoxified subjects, rather than in individuals with an established dependence who are currently abusing opioids.

A review of the role of anti-opioid peptides in morphine tolerance and dependence.

Studies on the mechanisms of tolerance and dependence have mostly focused on changes at the receptor level. These experiments, conducted with model systems ranging from clonal cell lines to whole animals, have identified a number of important adaptive mechanisms which occur at the receptor level. However, none of these adaptive mechanisms can completely account for the phenomena which serve to define the state of morphine tolerance and dependence, especially the observation that as an animal becomes more tolerant to morphine, less naloxone is required to trigger withdrawal. The data reviewed in this paper provide strong support for the hypothesis that the brain synthesizes and secretes neuropeptides which act as part of a homeostatic system to attenuate the effects of morphine and endogenous opioid peptides. According to this model, administration of morphine releases anti-opioid peptides (AOP), which then attenuate the effects of morphine. As more morphine is given, more AOP are released, thereby producing tolerance to the effects of morphine. Cessation of morphine administration, or administration of naloxone, produces a relative excess of anti-opioid, which is in part responsible for the withdrawal syndrome. Since endogenous and exogenous antagonists might together produce synergistic effects, less naloxone might be required to trigger withdrawal in the presence of higher levels of AOPs. Although the study of AOP is in its infancy, a deeper understanding of the central nervous system (CNS) anti-opioid systems may lead to new treatments for chronic pain, substance abuse, and psychiatric disorders.

Morphine dependence in rats with medial forebrain bundle lesions.

Rats with posterior medial forebrain bundle (PMFB) lesions and control rats were administered morphine chronically for 4 or 5 days via implanted subcutaneous silicone reservoirs. Following cessation of morphine administration after five days, PMFB rats showed less withdrawal-induced weight loss than control rats. Other PMFB and control rats were subjected to forced drinking of morphine solution for 9 days. PMFB rats consumed the morphine solution much more readliy than control rats, whereas intake of a quinine solution was similar in two other PMFB and control groups. These results suggest that the addictive and dependence properties of morphine may have separate mechanisms and based on previously reported neurochemical effects of PMFB lesions, that biogenic amines may be differentially involved in such mechanisms.