Opioid-induced Respiratory Depression: Are 5-HT_4a Receptor Agonists the Cure?

Since ancient times, physicians have faced the clinical dilemma of how to relieve a patient’s pain and suffering without doing additional harm. Although modern anesthesia and pain management have led the way in refining our use of opioid analgesics and developing exciting techniques of neural blockade, current therapies often remain inadequate to control severe debilitating pain. Illustrating this problem, a recently published survey assessing the prevalence of pain in the US finds 57% of adults have experienced chronic or recurrent pain in the last year, and 84% of those who suffered pain said they would rate their pain from moderate to severe (1). Consequently, almost six out of ten persons surveyed responded that they would be willing to pay more taxes to increase federal funding for scientific research into the causes and treatment of pain (1). Moreover, physicians are now compelled to properly treat a patient’s complaints of pain or risk both ethical and legal sanctions (2). Opioid analgesics, in particular μ-opioid receptor agonists, continue to be the mainstay of treatment for acute pain, acute postoperative pain, and are also widely used in the treatment of various chronic pain syndromes. However, unwanted side effects including central nervous system depression, with associated respiratory depression, can severely limit the physician’s ability to manage acute and chronic pain states even if adequate pain relief has been achieved. Independent of the route of administration (e.g., transdermal, transmucosal, subcutaneous, im, iv, epidural, or intrathecal), opioid-induced respiratory depression leading to hypoventilation and hypoxemia has produced irreversible neurologic injury and death and therefore remains one of the most serious complications in perioperative care (3). Evidence from experiments in animals suggests that the mechanism is a consequence of μ-opioid receptor–mediated blockade of specialized respiratory neurons in the brainstem (4). Although δ-opioid receptors have been investigated as an alternate therapeutic target in an attempt to separate a desired analgesic effect from opioid-induced respiratory depression, the data are not yet conclusive on the role of these receptor subtypes [for a recent review of the different opioid receptor types see (5)]. In addition, other therapeutic strategies that seek to reduce opioid dose requirements but retain analgesic efficacy are under investigation, such as using small doses of ketamine to counteract opioid-induced tolerance and hyperalgesia (6). Among the most exciting developments in this area of research is a study recently reported by Manzke and coworkers (7), who investigated the potential of the serotonin (5-hydroxytryptamine, 5-HT) receptor subtype 5-HT_4a (5-HT_4aR) as a therapeutic target for the treatment or prevention of opioid-induced respiratory depression. Manzke and colleagues hypothesized that a 5-HT_4aR–selective agonist might function to oppose μ-opioid receptor–mediated respiratory depression. This hypothesis is based on the fact that both the 5-HT_4aR and the μ-opioid receptors belong to a family of G protein–coupled receptors (GPCRs) that can modulate the concentration of adenosine 3′,5′-monophosphate (cAMP): stimulation of 5-HT_4aR increases intracellular cAMP concentrations whereas μ-opioid receptor stimulation decreases cAMP concentrations. In addition, both receptors appear to have overlapping expression patterns especially in the pre-Bötzinger complex (PBC), an area in the brainstem that contains respiratory neurons controlling respiratory rate. Although their hypothesis is compelling, there are several important considerations that must be addressed to both confirm and translate the observations made by Manzke and colleagues into a clinically relevant therapeutic strategy.

5-HT is a critical neurotransmitter that plays a key role in controlling a large variety of sensory and motor functions. Its effects are mediated through 5-HT receptors, of which seven distinct families (5-HT_1–7R) exist. Except for 5-HT₃R, which acts as a ligand-gated ion channel, all 5-HT receptors belong to the family of GPCRs although they do not share the same second messenger system [for a comprehensive review see (8)]. 5-HT_4aRs, which occur as the alternately spliced species 5-HT_4a–e, have a wide tissue distribution that includes the brain, gut, and the heart, as demonstrated through radioligand binding studies (9). Manzke and colleagues (7) provide immunohistochemical evidence that the 5-HT_4aR isoform is expressed in the ventrolateral medulla and they interpret their multilabeling results as proof of expression in respiratory neurons of the PBC. 5-HT₄Rs have also been consistently found in the nigrostriatal and mesolimbic systems of the brain (10). Outside the brain, significant expression of 5-HT_4aR has been described in the atrium (but not in the ventricle of the heart) and in the gastrointestinal tract. These observations together with the data provided by Manzke et al. support a contribution of 5-HT₄R–mediated effects not only to respiratory pattern generation, but also to a wide variety of physiologic functions including memory and learning, anxiety and depression, heart rate control, and gut motility. Because the effects on memory and learning as well as anxiety and depression are difficult to assess in animal studies, thorough investigation in human subjects will be necessary. At this point, there are not enough data to predict the side-effect profile of 5-HT₄R agonists in humans. In addition, it is unclear just how specific BIMU8, the agonist used by Manzke and coworkers, is for the 5-HT₄R. Several investigations suggest that BIMU8 is a nonselective agonist, and, in particular, has effects on 5-HT₃Rs, and furthermore, facilitates both dopamine and acetylcholine release in rat brain (9, 11, 12). There is ample evidence from earlier studies that supports the involvement of serotoninergic receptors of different subtypes in modulation of respiratory activity (13–15). Experimental use of newly described 5-HT₄R agonists (i.e., TS-951) and antagonists will help to further distinguish the roles of 5-HT4R-specific and other receptor subtype-specific effects on ventilation (16, 17). In addition, it will be necessary to determine whether any of the investigated compounds have intrinsic pro- or antinociceptive properties. For example, although not conclusive, there is evidence that BIMU8 has analgesic properties, at least at high concentrations (11–13, 18). In order to confirm the hypothesized mechanism that a 5-HT_4aR agonist-mediated increase in cAMP is the basis of reversal of opioid-induced respiratory depression, it would be very powerful to demonstrate the 5-HT_4aR-specific reversal of opioid-induced reduction of neuronal activity at the single-cell level. Manzke and colleagues provide whole-cell recording data from a single inspiratory neuron and provide single-cell RT-PCR results (7); however, they do not demonstrate the opioid effect on respiratory activity at the single-cell level. In our view, this experiment would not only undoubtedly establish the mechanism of opioid-induced respiratory depression, but also provide the basis to test the importance of GPCRs on regulating cAMP concentrations as a basis for treatment of opioid-induced respiratory depression. Because 5-HT_4aR agonists like BIMU8 reverse respiratory depression––presumably by increasing cAMP concentrations, as demonstrated by Manzke et al.––one would expect that this effect could be imitated by other agents that also increase cAMP in the same model system. Furthermore, it should be possible to use available 5-HT_4aR–selective antagonists or other agents that decrease the concentration of cAMP to produce depression of neuronal activity that mimics the opioid-induced effects on inspiratory neurons.

Despite these concerns, there remains ample evidence to support the hypothesis put forward by Manzke and colleagues (7). Their study has been widely received with the appropriate enthusiasm. As mentioned earlier, there is indeed a great need to improve patient safety during opioid treatment and also to make pain therapy more effective. Finding a cure for opioid-induced respiratory depression would certainly be a tremendous improvement. However, it may be premature to announce a major breakthrough, because the mechanism has not been clearly identified and there is no data yet on the feasibility of this approach in patients. Developing highly selective 5-HT_4aR agonists would likely provide very promising tools to further clarify the cellular mechanisms of respiratory control. These new agonists might become potential candidates for therapeutic interventions.

• © American Society for Pharmacology and Experimental Theraputics 2004

Mark A. Schumacher, PhD, MD, is an Associate Professor in the Department of Anesthesia and Perioperative Care and holds a joint appointment in the Department of Oral and Maxillofacial Surgery, University of California, San Francisco. MAS received his PhD in Physiology and Pharmacology as well as his MD from the University of California, San Diego. After an anesthesia residency and a pain research fellowship both at UCSF he joined the faculty UCSF Medical School. In addition to serving as an attending on the acute pain management service, he is leading a research team to investigate the molecular biology and physiology of pain transduction in the peripheral nociceptor.

Helge Eilers, MD, is an Assistant Professor in the Department of Anesthesia and Perioperative Care, University of California, San Francisco. He received his MD at the University of Bonn, Germany and completed his anesthesia residency training at UCSF. He collaborates with MAS in the study of the molecular biology and physiology of pain transduction in the peripheral nociceptor. His research focuses on the study of ion channel physiology, in particular ion channels involved in mechanotransduction as well as the study of subunit interactions. Please address correspondence to HE. E-mail eilersh{at}anesthesia.ucsf.edu; fax 415-514-0185.