Buprenorphine-Induced Changes in Mu-Opioid Receptor Availability in Male Heroin-Dependent Volunteers A Preliminary Study

Abstract

Medications for the treatment of substance abuse may be developed for a variety of purposes (e.g., ameliorate toxicity, treat overdoses) but a primary goal is to attenuate the subjective, behavioral, or physiological effects of the drug of abuse. Buprenorphine is a high affinity, mu opioid partial agonist, with kappa antagonist action (Cowan et al. 1977;Heel et al. 1979;Lewis et al. 1983). This compound is being evaluated as an alternative to methadone maintenance and detoxification in the treatment of opioid dependence (Bickel and Amass 1995). Buprenorphine's mu receptor ( OR) agonist actions could reduce opiate craving and prevent withdrawal, thus improving compliance with treatment compared to conventional opiate receptor antagonists (e.g., naltrexone). At the same time, its partial efficacy and high affinity at OR's provide long lasting functional antagonism, making it an effective means of blocking the effects of abused opiates. This unique combination of NO . 3 Buprenorphine and Mu Receptor 327 pharmacological properties confers potential advantages, including enhanced safety over existing medications for treating opioid abuse (Lange et al. 1990).Buprenorphine sublingual (SL) liquid has been shown to decrease heroin self-administration in singledose human laboratory studies (Mello and Mendelson 1980;Mello et al. 1981Mello et al. , 1982; the dose-dependency of its effects on reinforcement has been less well characterized. In a clinical study, Johnson et al. (1995) compared the short-term efficacy of placebo, 2 and 8 mg/day buprenorphine in a parallel group, randomized design during a two-week initial maintenance period. In this study, active doses were more effective than placebo in decreasing heroin use, however, there were no differences in therapeutic efficacy between 2 and 8 mg. Schottenfeld et al. (1993) used a within-subject study design in which heroin-dependent outpatients received ascending/descending maintenance doses of buprenorphine ranging from 2 to 16 mg/day. Sixteen milligrams produced significant decreases in opioid-positive urine samples, relative to lower doses. Thus, available data suggest that, relative to placebo, buprenorphine doses ranging from 2 to 8 mg are equally capable of decreasing opioid use, whereas doses of 16 mg have greater efficacy. This may suggest that the effect of buprenorphine in decreasing opiate self-administration may not be dose-dependent, at least in lower dose ranges. In fact, in a recently completed laboratory study in heroindependent volunteers, maintenance doses of 2, 4, and 8 mg buprenorphine showed equal efficacy in decreasing the reinforcing effects of hydromorphone (Greenwald et al. 1999).On the other hand, laboratory studies have demonstrated that SL buprenorphine blocks many of the subjective effects of hydromorphone, a full mu opioid agonist, in a dose-dependent manner. For instance, Bickel et al. (1988) showed that maintenance on buprenorphine (2, 4, 8, 16 mg) produced dose-related decreases in subjective effects to cumulative hydromorphone (0, 6,...

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

“…Common phMRI activation was observed in a number of brain regions for the higher doses of buprenorphine (i.e., 0.1 mg/kg and 0.2 mg/70 kg for rat and human, respectively). These regions included the somatosensory cortex, cingulate, insula, thalamus, striatum, hippocampal formation, periaqueductal gray, and cerebellum, which are all implicated in pathophysiological conditions that include pain (Elman et al, 2011;Borsook, 2012;Tracey and Dickenson, 2012) and have high densities of opioid receptors (Zubieta et al, 2000;Peng et al, 2012). Thus, in large part, the phMRI signature for buprenorphine was observed to translate between conscious, naive rodents and healthy human subjects in a dose-dependent manner.…”

“…Imaging techniques are being increasingly used as translational neuroscience tools, particularly in drug discovery and development efforts. Methods such as PET and SPECT are useful when characterizing a central nervous system disease state (eg, b-amyloid build up in patients with Alzheimer's disease (Nordberg, 2004) or dopaminergic terminal function in patients with Parkinson's disease (Sawle et al, 1993;Marek et al, 1996) and also as a means to determine whether a pharmacological compound has engaged its target [eg, buprenorphine at m-opioid receptor (Zubieta et al, 2000) or aprepitant at NK-1 receptors (Keller et al, 2006)]. Proving the presence of specific target in a preclinical model or disease state and robust target engagement are extremely important to determine.…”

Buprenorphine Antinociception is Abolished, but Naloxone-Sensitive Reward is Retained, in μ-Opioid Receptor Knockout Mice

“…Since the rewarding effects of buprenorphine are likely to be mediated by d-and k-opioid receptors in addition to m-opioid receptors, buprenorphine might conceivably provide a prototype for clinical effectiveness through decreased m-opioid receptor availability (Greenwald et al, 2003;Zubieta et al, 2000). Such m-opioid receptor-selective partial agonists might even provide good adjuncts during detoxification.…”

Positron Emission Tomography Molecular Imaging of Dopaminergic System in Drug Addiction

“…Zubieta et al (2000) reported an increase in l receptor availability in the VTA, inferofrontal cortex, and anterior cingulate in heroin-dependent subjects compared with control subjects using [ 11 C] carfentanil PET. Kling et al (2000) performed a study using [ 18 F] cyclofoxy, an opioid antagonist that labels l and j opioid receptors, in methadone maintained heroin-dependent subjects.…”