Use of in vivo apparent pA2 analysis in assessment of opioid abuse liability

doi:10.1016/0165-6147(92)90086-L

Trends in Pharmacological Sciences

Volume 13, 1992, Pages 282-286

https://doi.org/10.1016/0165-6147(92)90086-L Get rights and content

Abstract

Abuse liability testing of opioid drugs was originally motivated by attempts to separate the analgesic effects of opioids from their likelihood for abuse. It has become apparent that the human population group likely to abuse opioids has little overlap with the population group requiring opioids to treat pain, therefore there is no longer a need to separate these two properties of opioids. This is fortunate, since, as reviewed here by Jim Woods and colleagues, the results of the plethora of studies that have attempted to distinguish these two properties in known opioids strongly indicate that they are inseparable. Evaluation of the abuse potential of novel opioids remains, however, critically important in deciding on governmental restrictions on their accessibility. In addition, opioid abuse liability testing contributes enormously to our understanding of the behavioral mechanism of action of these drugs, and in surprising and helpful ways has increased our appreciation of the various test systems used to garner information about them.

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Citation Excerpt :
We evaluated the antagonists (see Table 1) βCCT (α1GABAA-preferring, Huang et al., 2000); 3-PBC (α1GABAA-preferring; Harvey et al., 2002); and XLi-093 (α5GABAA-selective; Li et al., 2003). When rightward shifts in the triazolam self-administration dose–effect functions were evident, these results were analyzed using in vivo apparent pA2 analysis (Rowlett et al., 2005; Tallarida, 2000; Woods et al., 1992). This analysis enabled us to quantitatively analyze the potency of the antagonists and to draw conclusions or hypotheses about a role for particular receptor subtypes in the reinforcing effects of benzodiazepines.
Conventional benzodiazepines bind non-selectively to GABA_A receptors containing α1, α2, α3, and α5 subunits (α1GABA_A, α2GABA_A, α3GABA_A, and α5GABA_A receptors, respectively), and the role of these different GABA_A receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABA_A receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam.
Rhesus monkeys (n = 4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose–response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), βCCT and 3-PBC (α1GABA_A-preferring antagonists), and XLi-093 (α5GABA_A-selective antagonist).
Flumazenil, βCCT and 3-PBC shifted the dose–response functions for triazolam to the right in a surmountable fashion, whereas XLi-093 was ineffective. Schild analyses revealed rank orders of potencies of flumazenil = βCCT > 3-PBC. Comparison of potencies between self-administration and previous binding studies with human cloned GABA_A receptor subtypes suggested that the potencies for βCCT and 3-PBC were most consistent with binding at α2GABA_A and α3GABA_A receptors, but not α1GABA_A or α5GABA_A receptor subtypes.
Our findings were not entirely consistent with blockade of α1GABA_A receptors and are consistent with the possibility of α2GABA_A and/or α3GABA_A subtype involvement in antagonism of the reinforcing effects of triazolam. The α5GABA_A receptor subtype likely does not play a substantial role in self-administration under these conditions.
Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists
2011, Journal of Neuroscience Methods
Citation Excerpt :
This is a measure of the absolute potency of the antagonist, which is also the apparent antagonist pA2 (negative logarithm of the antagonist concentration (or dose) required to produce a 2-fold increase in the agonist concentration (or dose) required to induce a defined magnitude of response). Occasional reports have provided pA2 values that have been used to identify the receptor subtypes mediating the discriminative stimulus effects of opiates (Bertalmio and Woods, 1987; Woods et al., 1992), and the self-administration of alfentanil (Bertalmio and Woods, 1989), heroin (Rowlett et al., 1998) and benzodiazepines (Paronis and Bergman, 1999), all of which are direct receptor agonists. The theory of competitive antagonism assumes that the competitive antagonist and the agonist bind reversibly to the same site.
Competitive dopamine receptor antagonists accelerate psychomotor stimulant self-administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self-administration paradigm this is assumed to be the satiety threshold or C_min. The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function of antagonist dose should reflect the antagonist pharmacodynamic potency. The time course of this effect should reflect the rate of change of antagonist occupancy of receptors and, therefore, antagonist concentration, i.e. pharmacokinetics. Rats self-administered apomorphine or cocaine at a stable rate and were then injected i.v. with one of four competitive D₁-like or D₂-like dopamine receptor antagonists and the session continued. The agonist concentrations at the time of each self-administration (satiety thresholds) were calculated during the session. The antagonists accelerated self-administration of both agonists with a concomitant increase in the calculated satiety thresholds. The maximum agonist concentration ratio was proportional to the dose of antagonist. The time courses of the changes in agonist concentration ratio were independent of the agonist and of the dose of antagonist. Schild analysis of the maximum agonist concentration ratio as a function of the antagonist dose allowed apparent pA₂ (or K_dose) to be measured. Antagonist K_dose values should provide a quantitative basis for receptor identification in behavioral pharmacology. The assay system may also measure the pharmacokinetics of antagonist elimination from the brain. Agonist self-administration represents a sensitive in vivo pharmacological assay system that provides information useful for pharmacokinetic/pharmacodynamic modeling of antagonist effects.
In Vitro and In Vivo Assessment of Mu opioid receptor constitutive activity
2010, Methods in Enzymology
Citation Excerpt :
Of the naloxone and naltrexone related compounds we have tested, the majority of them reduce the morphine effect by ~ 50% within 3–5 min and produce near maximal blockade within 10 min. More involved methods are available to estimate antagonist potency including in vivo apparent pA2 analysis (Walker et al., 1994; Woods et al., 1992). An example of this approach using naltrexone analogs is depicted in Fig. 21.9.
Constitutive (basal) signaling has been described and characterized for numerous G protein coupled receptors (GPCRs). The relevance of this activity to disease, drug discovery and development, and to clinical pharmacotherapy is just beginning to emerge. Opioid receptors were the first GPCR systems for which there was definitive evidence presented for constitutive activity, with numerous studies now published on the regulation of this activity (e.g., structure/activity of the receptor as it relates to basal activity, pharmacology of ligands that act as agonists, inverse agonists and “neutral antagonists,” etc.). This chapter summarizes some of the methods used to characterize constitutive activity at the mu opioid receptor (MOR) in preclinical in vitro and in vivo model systems. This includes cell-based systems that are useful for higher throughput screening of novel ligands and for studying variables that can impact basal tone in a system. In vivo assays are also described in which constitutive activity is increased in response to acute or chronic opioid agonist exposure and where withdrawal is precipitated with antagonists that may function as inverse agonists or “neutral” antagonists. The methods described have inherent advantages and disadvantages that need to be considered in any drug discovery/development program. A brief discussion of progress toward understanding the clinical implications of MOR constitutive activity in the management of opioid addiction and chronic pain is also included in this chapter.
Chronic pain, substance abuse and addiction
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Guidelines and methodological reviews concerning drug abuse liability assessment
2003, Drug and Alcohol Dependence
Regulatory control of drugs with abuse liability is an important component of drug control policy and is believed to help prevent nonmedical use. To be maximally effective, this requires a scientific assessment of abuse liability of drugs considered for regulatory control. These assessments have relied extensively on laboratory-based animal and human testing, but also utilize information from clinical trials, actual abuse and other sources. Here, we discuss recommendations and guidelines that have been proposed for abuse liability assessment and describe important review papers and conference proceedings that have addressed this matter, focusing primarily on drugs with medical usefulness. Historically, there is substantial consensus about how to approach abuse liability evaluation of drugs with actions similar to those of abused opiates, stimulants, depressants, and to a somewhat lesser extent, cannabinoids and hallucinogens, and much of what has been recommended for abuse potential assessment in the past remains valid and useful. On the other hand, novel CNS-active medications which cannot be readily classified with these traditional drugs of abuse are increasingly under development. In addition, advances in the science of abuse liability assessment need to be incorporated into future guidelines and recommendations on this subject. Developers of new medications need guidance on how to utilize scientific research to maximize therapeutic benefit while minimizing risk for abuse. Thus, another goal of this review has been to identify areas where critical thinking and new guideline development are needed.
Pain responses in methadone-maintained opioid abusers
2000, Journal of Pain and Symptom Management
Providing pain management for known opioid abusers is a challenging clinical task, in part because little is known about their pain experience and analgesic requirements. This study was designed to describe pain tolerance and analgesic response in a sample of opioid addicts stabilized in methadone-maintenance (MM) treatment (n = 60) in comparison to matched nondependent control subjects (n = 60). By using a placebo-controlled, two-way factorial design, tolerance to cold-pressor (CP) pain was examined, both before and after oral administration of therapeutic doses of common opioid (hydromorphone 2 mg) and nonsteroidal anti-inflammatory (ketorolac 10 mg) analgesic agents. Results showed that MM individuals were significantly less tolerant of CP pain than control subjects, replicating previous work. Analgesic effects were significant neither for medication nor group. These data indicate that MM opioid abusers represent a pain-intolerant subset of clinical patients. Their complaints of pain should be evaluated seriously and managed aggressively.

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Trends in Pharmacological Sciences

Use of in vivo apparent pA2 analysis in assessment of opioid abuse liability

Abstract

Life Sci.

Drug Alcohol Depend.

Eur. J. Pharmacol.

Life Sci.

Drug Alcohol Depend.

Drug Alcohol Depend.

Pharmacol. Biochem. Behav.

Drug Alcohol Depend.

J. Pharmacol. Meth.

J. Am. Med. Assoc.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Use of in vivo apparent pA₂ analysis in assessment of opioid abuse liability