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The Role of Endogenous Morphine and Nitric Oxide in Pain Management

The discovery of dysfunction of endogenous morphine, which leads to the development of many chronic pain conditions, may lead to promising new safe and effective treatments.
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It has been more than 30 years since morphine was discovered to be an endogenous signal molecule in the body.1 Since then, the word ‘endorphin’ has been adopted as an abbreviation of ‘endogenous morphine,’ referring to both morphine peptides and morphine itself. Endogenous opiates are released via the descending corticospinal tract, allowing for the body to mediate its own analgesia.2 Osteopathic manipulative therapy (OMT) has been found to initiate release of nitric oxide (NO), endogenous morphine’s second messenger in the body.3,4

This article discusses the many different effects endogenous morphine and NO have on the body and their specific mechanisms. These mechanisms are being investigated as the underlying mechanism of OMT.

Endogenous Morphine In the Brain

Endogenous morphine acts as a neurotransmitter that readily crosses the blood-brain barrier into the cerebrospinal fluid.5 In the brain, morphine binds to several classes of G-protein-related membrane receptors, one of which is the m-opioid receptor (MOR). The MOR is a Gi-coupled protein that inhibits adenylyl cyclase, down-regulating cell metabolism.6 The expression of the MOR is altered by levels of stress, as demonstrated in vitro with rats.1 These receptors are concentrated in specific regions of the brain, including the nucleus caudatus, nucleus putamen, nucleus accumbens, and other cortical areas, as well as the limbic system (amygdala, hypothalamus, and thalamus).7 Endogenous morphine binding to the MOR on γ-aminobutyric acid (GABA) B interneurons stimulates release of constitutive NO, disinhibiting dopamine output.8 This mechanism blocks the stress response, which has been observed in the ventral tegmental area of rats.1 Oken et al noted that “dopamine release in the nucleus accumbens as demonstrated with radionuclide PET scanning was found to be directly correlated with degree of placebo analgesia.”9 

Mechanism of OMT

The sensation of pain is processed in the thalamus. As noted, endorphins are released via a descending corticospinal tract, allowing the body to mediate its own analgesia.2 This exemplifies the second tenet of osteopathic medicine: the body has an innate ability to heal itself.10

A number of studies have demonstrated that OMT releases vasculature and nerve tissues, causing a marked increase in the concentration of NO in the blood. It may also be noted that administration of nitrous oxide increases the beneficial effects of joint manipulation.11 NO is a free radical that diffuses freely through cell membranes. It has the unique property of being the only gas-phase neurotransmitter.7 NO is believed to have antiviral and antibacterial properties, in addition to its function in mediating the stress and relaxation responses. This effect is associated with co-release of endogenous cannabinoids, such as anandamide and 2-arachidonylglycerol.3 NO also is a potent vasodilator and an apoptotic molecule that orchestrates wound healing. During injury repair, NO maintains a cytostatic state and decreases collagen deposition, preventing the ropy tightness observed in patients with somatic dysfunctions. This shows a cross-communication between pro-inflammatory, mitogenic, and apoptotic pathways.12

OMT is believed to modulate the shape and growth of fibroblasts. In a somatic dysfunction, hyperplasia is favored. If this dysfunction is corrected and heals, damaged cells undergo apoptosis and are removed. In 2006, using a cell culture stretching machine (Flexercell FX-2000), Dodd et al showed that fibroblast cultures exposed to 10% strain for 72 hours produced NO in concentrations 3 times higher than did cells under no strain.12 In fact, siginificantly increased levels of NO were observed starting as early as the 24 hour mark. After only 3 hours of strain, the fibroblasts migrated into a cluster and altered their shape by eliminating actin-containing pseudopodia. They also underwent hyperplasia, contributing to the characteristic ropy tissue texture changes and decreased range of motion that are noted by the osteopathic physician. These changes persist even after the strain has been removed. These findings led John McPartland, DO, to predict that “there is no doubt that future research collaborations will open new doors for the osteopathic physicians’ use of osteopathic manipulative treatment.”13 

Endogenous Morphine in Psychiatry

What makes pain such a unique sensory experience is its close link to emotional responses. As Salamon et al stated in 2006, “Pain....can be altered by past experiences, societal beliefs, and emotional states.”2 This was shown when amygdala lesions were discovered to increase pain thresholds. Since the amygdala anatomically is one of the emotional centers of the brain, this indicates that there is a physical connection between pain and emotion, and according to the authors, this is evidence for a molecular source of clinical depression and pain. Whether the transmission between physical pain and emotional response is bidirectional is yet to be determined.

Just as endorphins can block pain, they can block the conscious mind from processing pain during traumatic events.2 This proposes a molecular mechanism to explain psychiatric repression. With endorphins playing a role in blocking the pain of traumatic events, it is logical that the absence of endogenous morphine would precipitate psychiatric morbidity, such as depression and post-traumatic stress disorder (PTSD).14 “Endogenous morphine expression and morphine’s interaction with its major precursor, dopamine, strongly suggests that endogenous morphine systems are reciprocally dysregulated in schizophrenia and major psychiatric illnesses.”1 For example, cerebral spinal fluid taken during psychotic episodes showed elevated levels of opioid beta endorphins in patients with bipolar disorder, post-partum psychosis, and schizophrenia. Levels return to baseline when the patient recovers.1 Therefore, we would argue that pain syndromes attributed to psychiatric illnesses could be caused by incorrect levels of endogenous morphine or an error in processing it.

Last updated on: October 15, 2014
First published on: October 1, 2014