Endorphinergic Attenuation of Distress by Concomitantly Enhancing Endogenous Opioid Release and Switching Opioid Receptor Signaling from an Excessively Excitatory to a Normal Inhibitory Mode

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 naïve 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 G s-coupled to inhibitory G i /G o-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 naïve 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.

Emotional and Physical Distress Relief Using a Novel Endorphinergic Formulation

“…The present report is focused on the nutraceutical agents used in these trials, all of which are considered as Generally Recognized as Safe (GRAS) by the FDA and do not require further FDA approval or a prescription. While our findings were generally consistent among all agents studied, this analysis highlights caffeine (100 mg), a PDE inhibitor that enhances endorphins by boosting cAMP levels (Endorphin Enhancer), combined with N-acetylcysteine (NAC) (600 mg), an amino acid that metabolizes into sodium sulfate thereby switching opioid receptors from an excitatory to inhibitory mode (Opioid Receptor Switcher) [17].…”

“…The final 60 participants (38 males, 22 females; ages 18 -86) went through each experimental condition, separated by at least a two-day "wash-out" period. A variety of Endorphin Enhancer and Opioid Receptor Switcher agents (and doses) were assessed in these trials, using Crain and Crain's rationale for selection of appropriate agents in each class [17,[19][20][21]. The present report is focused on the nutraceutical agents used in these trials, all of which are considered as Generally Recognized as Safe (GRAS) by the FDA and do not require further FDA approval or a prescription.…”

“…Exogenous opioid drugs, such as oxycodone, hydrocodone, and morphine, are the most widely prescribed medications in history, and their use, both legal and illegal, continues to escalate [27]. However, their noxious and even life-threatening side effects, including tolerance, dependence, and addiction, are wellknown [28], and appear to result from their dysfunctional impact on the endogenous opioid system, including protracted excitatory receptor signaling and endorphin depletion [16,17,29], thereby producing EDS [17]. In addition, the extensive use of acetaminophen may also contribute to the development of EDS since it tends to lower sulfate levels [30], which may result in excessive opioid receptor signaling, potentially involved in the wellknown hyperalgesic "rebound headache" syndrome.…”

“…The preclinical nerve tissue research of Crain and Shen [15,16] over the past three decades on the function of opioid receptors in the pain response may provide critical insights into these issues with important clinical implications [17]. They discovered that whereas opioid receptors are normally in an inhibitory mode, thereby producing analgesia when triggered by the release of endorphins, opioid receptors could also be switched to an excitatory mode, which literally stimulates the opposite effect, that is, hyperalgesia, or increased pain sensitivity.…”

“…These studies demonstrated, for the first time, that the pain-relieving power of endorphins could be unmasked when opioid receptors are switched to the inhibitory mode. Crain and Crain [17] provide an extensive review of these preclinical pain studies on the bimodal nature of opioid receptor signaling in the endogenous opioid system and emphasize the significance of these studies in elucidating neuropharmacologic and neurochemical mechanisms that may mediate clinical distress disorders.…”