How to design an opioid drug that causes reduced tolerance and dependence

Abstract

Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.Opioids have been used to treat pain for well over 5,000 years. 1 Before the 19th century, the drug of choice was opium, the resin released from the seed pods of the opium poppy. The potency of opium varied greatly from batch to batch, making it impossible to standardize dosage and greatly increasing the risk of overdose. The purification of morphine from opium in 1803 finally solved this problem and greatly improved the safety of using opioids; however, once drug doses were easily quantifiable, the problem of tolerance, defined as the need for higher doses of drug to achieve the same effect, became increasingly apparent. Tolerance was frequently accompanied by physical dependence, the need for continued drug use to prevent somatic and affective withdrawal symptoms, and in some cases by addiction.Scientists have assumed, or at least hoped, that the biological mechanisms mediating opioid analgesia are distinct from, and can be divorced from, those mediating tolerance, dependence, and addiction, and from the time of morphine's discovery, they have tried to develop opioids with a reduced propensity to cause these negative sequelae of prolonged opioid use. Two hundred years later, however, morphine is still a mainstay of modern pain management, and Many attempts to develop a better opioid have been based on flawed or incomplete hypotheses of tolerance development. As a case in point, both heroin and sustained release oxycodone (trade name OxyContin), today 2 of the most highly sought after opioid drugs of ...

A Novel Knock-In Mouse Reveals Mechanistically Distinct Forms of Morphine Tolerance

“…As we and others have proposed previously, tolerance in WT mice is probably due to homeostatic compensatory changes in signal transduction downstream of the receptors that mask receptor activity in the presence of drug and manifest as withdrawal upon removal of the drug. One key homeostatic adaptation that contributes to morphine tolerance in WT mice is superactivation of adenylyl cyclase signaling (for review, see Nestler, 2004;Berger and Whistler, 2010). The importance of this adaptation not only to second messenger signaling but also to synaptic adaptations and behavioral withdrawal was recently demonstrated in vivo (Madhavan et al, 2010).…”

“…In particular, tolerance in DMOR mice is accompanied by down-regulation of receptors, whereas tolerance in WT mice is not. Several groups have proposed that tolerance to morphine in WT animals is caused primarily by compensatory homeostatic adaptations that mask the presence of morphine in the presence of drug and manifest as withdrawal upon removal of the drug (for review, see Nestler, 2004;Berger and Whistler, 2010). In contrast, tolerance mediated by loss of receptor function should produce little to no withdrawal upon removal of morphine, because removal of an agonist from a nonfunctional receptor should have no behavioral effect.…”

Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig

“…In myenteric neurons MOR is internalized in response to agonists including [D-Ala 2 , MePhe 4 , Gly(ol) 5 ]enkephalin (DAMGO), whereas morphine does not induce MOR endocytosis unless neurons have been chronically exposed to this opiate (40,43,59). The inability of morphine to induce endocytosis has led to the hypothesis that agonists that weakly promote internalization are expected to lead to tolerance and dependence (4). A recent review highlights that effective desensitization of signaling occurs in the absence of endocytosis and suggests that this model may not be entirely accurate (69).…”

Analgesic Effect and Immunomodulation Response on Pro-Inflammatory Cytokines Production by <i>Scrophularia megalantha</i> Extract

“…Also NSAIDs can aggravate peptic ulcers and cause hepatorenal complications. Consequently, there is renewed interest in new natural analgesics, especially of plant origin [1,2].…”