Abstract
The endogenous opioid system plays a significant role in the modulation of distress in many psychiatric, neurologic, and neurodevelopmental disorders. Many clinical distress symptoms show similarities to the excitatory autonomic withdrawal effects in chronic opioid-dependent animals and humans, as well as to the “quasi-morphine withdrawal syndrome” evoked in naive rodents shortly after acute systemic injection of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors. These symptoms result from excessive excitatory opioid receptor signaling and increased endorphin release. Pharmacologic analyses of the remarkably plastic bimodal (excitatory/inhibitory) signaling functions of opioid receptors have utilized microelectrode recordings from opioid-sensitive neurons in tissue cultures of mouse sensory ganglia and hot-water tail-flick assays in mice. These studies led to development of specific chemical formulations that switch opioid receptor signaling from an excessively excitatory to a normal inhibitory mode. Critical combinations of cAMP-PDE inhibitors that release endorphins plus specific agents that switch opioid receptors from excitatory Gs-coupled to inhibitory Gi/Go-coupled signaling were shown to attenuate hyperalgesia and distress evoked by diverse chemical stressors in mouse tail-flick assays. Both the “quasi-morphine withdrawal syndrome” in naive rodents as well as the excitatory withdrawal effects in chronic, opioid-dependent animals and humans may be manifestations of a common Endorphinergic Distress Syndrome (EDS). We suggest that many distress symptoms are caused by EDS, a dysfunctional imbalance in the endogenous opioid system, consisting of abnormal endorphin levels, together with opioid receptors predominately in their excitatory mode. Therefore, concomitantly enhancing endogenous opioid release and switching excessive excitatory opioid receptor signaling to inhibitory signaling can attenuate these distress symptoms. Trials of a critically formulated oral preparation, containing both endorphin enhancers and opioid receptor switchers, have resulted in long-term anxiolytic efficacy and enhanced calm and mental clarity in large numbers of individuals with distress symptoms. These endorphinergic formulations may provide treatment for the emotional and physical distress associated with many psychiatric, neurologic, and neurodevelopmental disorders.
Highlights
In a recent study of the effects of cyclic AMP-phosphodiesterase inhibitors in mice, Crain and Shen [1] emphasized Collier et al.’s [2,3] pioneering studies demonstrating that acute systemic injection of naïve rodents with a cAMP-PDE inhibitor, e.g., caffeine or theophylline, rapidly evokes a “quasi-morphine withdrawal syndrome” that is remarkably similar to naloxone-precipitated excitatory withdrawal effects in chronic morphine-dependent animals
Since the B-subunit is known to bind selectively, with high specificity, to the monosialoganglioside glycolipid, GM1 which is abundantly distributed on the external surface of neuronal cell membranes [20,21], these results suggested that GM1 ganglioside may regulate Gs-coupled excitatory opioid receptor signaling in sensory and perhaps other types of neurons [9,19]
Crain and Shen [1] confirmed this research by demonstrating that systemic (s.c.) injection in naïve mice of IBMX or caffeine (10 mg/kg) as well as a much lower dose (1 μg/kg) of a more specific cAMP-PDE inhibitor, rolipram [33], rapidly evokes thermal hyperalgesic effects that appear to be mediated by enhanced excitatory opioid receptor signaling, as occurs during withdrawal in opioid-dependent mice
Summary
In a recent study of the effects of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors in mice, Crain and Shen [1] emphasized Collier et al.’s [2,3] pioneering studies demonstrating that acute systemic injection of naïve rodents with a cAMP-PDE inhibitor, e.g., caffeine. The reliability and the validity of this antinociceptive assay and its specificity for analyzing opioid receptor signaling functions have been confirmed by elegant studies utilizing intra-spinal infusion of ultralow-dose naltrexone in morphine-treated rats [13,14] and correlative biochemical analyses of ultra-low-dose naloxone in morphine-treated rats [15,16] These studies in mice provided the scientific rationale for a successfulPhase III clinical trial on >700 chronic low-back pain patients with high-dose oxycodone plus ULDN (OxytrexTM), resulting in >50% decrease in physical dependence following sudden withdrawal of opioids after 12 weeks [17,18]
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