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.¹²In 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.
Mechanism of Pain Relief
Morphine, dopamine, and catecholamines all share aspects of their biosynthetic and metabolic pathways.¹The body uses levodopa (L-dopa) to make dopamine. L-dopa also is an intermediate in the production of endogenous morphine. From this mechanism, it can be further postulated that dopamine levels can dictate morphine conditions. One example of this is the increase in endogenous substances, including morphine, codeine, and tetra
hydropapaveroline in cerebral spinal fluid from patients being treated with L-dopa for Parkinson’s disease.¹⁵ Parkinson’s disease causes a large variety of pain syndromes.¹⁶ If dopamine levels and morphine levels are so intimately related, the dysfunction in dopamine in Parkinson’s disease may carry over to a dysfunction in morphine, causing pain syndromes in these patients.
Both the MOR and endocannabanoid receptors are coupled with nitric oxide synthase (NOS).⁴ These are just 2 of the many different pathways converging at NOS. Activated when Ca⁺² binds to it, NOS is an electron transporter containing flavin adenine dinucleotide and flavin mononucleotide. NOS oxidizes the amino acid arginine to produce NO. Although this mechanism theoretically validates the use of arginine as a supplement, no studies have been able to show any benefit from this practice.¹⁷
There are several kinds of NOS, including cNOS (constitutive NOS) and iNOS (inducible NOS). In addition, there are 2 types of cNOS—neuronal NOS (nNOS or NOS I) and endothelial NOS (eNOS or NOS III). Neuronal NOS produces NO in the nervous system. This type of NOS is associated with plasma membranes and Golgi bodies in neurons, playing a major role in central nervous system communication (Figure 1).¹⁸ NO downregulates neuron transmission by inhibiting Ca⁺² influx and activating K+ channels, causing hyperpolarization to prevent action potentials. This is how pain pathways are directly blocked by morphine via NO, mediating the relaxation response. Physiological changes, such as reduced metabolic rate, lower blood pressure, and stabilization of vital signs define the relaxation response. This response can be brought on automatically when a patient in acute distress performs a repetitive mental or physical task, such as repeating mantras or rocking oneself, while ignoring distracting thoughts.² It is possible that the relaxation response explains the mechanism for non-pharmaceutical treatment of pain, including meditation. Many lay people are familiar with the technique that entails rubbing the area around an injury, overloading the sensory ganglion with stimuli, thereby reducing pain. Perhaps this repetitive physical motion also prompts the relaxation response.
Fibromyalgia is a pain syndrome characterized by a high level of endogenous opioids in the cerebral spinal fluid. This is indicative of dysfunctional processing of endogenous opioids. Although fibromyalgia is largely considered idiopathic, Pall et al has attributed fibromyalgia, PTSD, chronic fatigue syndrome, and multiple chemical sensitivity to excess NO.¹⁹ Considerable evidence suggests that nitroxidative stress caused by NO itself can cause pain.²⁰ Therefore, NO has a paradoxical effect of pain palliation in appropriate concentrations in the body, while producing pain in larger concentrations. Current studies agree that fibromyalgia patients are under oxidative stress due to excess NO.¹⁹˒²⁰˒²¹ Oxidative stress may be treated with antioxidants, balneotherapy (bathing), and mind-body therapies that elicit the relaxation response.²¹ A study in 2010 looked at the use of antioxidant synthetic enzymes, nicknamed synzymes, to eliminate this oxidative stress.²⁰ These synzymes may offer a promising future in the treatment of pain syndromes such as fibromyalgia.
Anti-Inflammatory Properties of Morphine
Morphine has also been shown to have anti-inflammatory effects via NOS found on the surface of cells in both the immune and cardiovascular systems that require activation by Ca⁺². In 2005, Zhu et al showed that, through NOS, morphine inhibits activation of immune cells.²² Inactive immune cells are round, whereas active immune cells are amoeboid (Figure 2).
Cell shape can be mathematically described as the cell’s form factor (Figure 3), with a form factor of 1 indicating a perfectly circular cell (inactive) and a form factor of 0 indicating a completely non-circular cell (active). When treated with morphine, form factor indicates that the cells are inactive, whereas untreated cells are active. This has been demonstrated in blood cells from Mytilus, a bivalve.²²After morphine treatment for 24 hours, the form factors of Mytilus hemocytes measure on average between 0.7 and 0.9. Untreated Mytilus hemocytes have a form factor of 0.1 to 0.6.
This anti-inflammatory effect possibly is caused by dopamine, since dopamine-receptor antagonists can block morphine-induced immunomodulation. Dopamine can both activate and suppress cytokine release, depending on what cell is stimulated. Cytokines that are released by dopamine stimulation include interleukin (IL)-1, IL-6, tumor necrosis factor, and interferon. Immune down-regulation from this pathway is an anti-inflammatory response that contributes to pain relief, but also may leave patients vulnerable to infection.² As Stephen C. Pryor, PhD, teaches, parasites, such as Ascaris, take advantage of this mechanism to remain unnoticed by the host’s immune system.23 These parasites have been found to release morphine to evade host immune response.²³
Vasodilation Action
Like all medications, morphine has side effects. Morphine’s side effects are caused by stimulation of receptors outside the target pathway. One well-studied side effect of morphine is hypotension, as NO causes vasodilation. As part of the relaxation response, this side effect may be desirable. Vasodilation occurs via eNOS. NO activates guanylate cyclase, inducing release of cGMP. In turn, a cGMP-dependent kinase, uses the cGMP to inhibit muscle contraction.⁴ This smooth muscle relaxation causes vasodilation, lowering blood pressure.
Vasodilation also functions endogenously to activate bradykinin and inhibit platelet aggregation. Bradykinin is a neurotransmitter that causes the sensation of pain. One kind of bradykinin nociceptor has the ability to self-regulate, altering subsequent painful stimuli. These receptors often amplify painful stimuli, resulting in the hyperalgesia observed in diabetic neuropathy. If endogenous opiates are released, this pain is blocked from entering ascending tracts to the thalamus.² NO can also inhibit platelet function. This causes an increase in bleeding time observed in newborns treated with inhaled NO.²⁴
To date, the Food and Drug Administration has approved inhaled NO (iNO) for infants suffering from persistent pulmonary hypertension of the newborn (PPHN). iNO increases the ventilation perfusion (V/Q) ratio by vasodilating the alveolar capillaries it encounters. As it continues in the bloodstream, NO also decreases the pulmonary artery pressure, thereby decreasing the need for extracorporeal membrane oxygenation (ECMO), and, subsequently, death in term and late-preterm newborns with severe PPHN. When 20 ppm of iNO is administered, O² saturation improves by 20% within 20 minutes. This also has been used off-label in adults with acute respiratory distress syndrome, but no research has been able to support the efficacy of this practice.²⁴
Morphine and Physical Dependence
Perhaps the most studied side effect of morphine is physical dependence. Many different substances of abuse, including cocaine, alcohol, and nicotine share a mechanism of action via the release of endogenous morphine.¹ The nucleus accumbens is part of the dopamine-based reward pathway in the brain that has been found responsible for physical dependence. The MOR’s primary function in the nucleus accumbens is its ability to block dopamine reuptake, causing physical dependence.²NO may aid in preventing physical dependence because NOS inhibitors have been demonstrated to reduce opioid analgesic tolerance.²⁵ In a study that used transdermal nitroglycerine patches to generate NO as coadjuvant therapy to morphine in patients with cancer pain, patients treated with both the patch and morphine reported lower pain scales and subsequently needed lower doses of morphine for analgesia compared with patents using morphine alone. In this study, the daily primary treatment drug was 50 mg of oral amitriptyline; the co-adjuvant therapies were oral morphine 80-90 mg and a nitroglycerine 5 mg transdermal patch.²⁶ Therefore, NO has a potential use in pain management as a preventive measure for physical dependence and sedation by allowing for lower dosage of morphine.²⁵˒²⁷
Related phenomena include the off-label use of iNO for pain of sickle cell crisis. In 2 randomized, single-center, placebo controlled trials with a total of 38 subjects, patients who were administered iNO had lower pain scores and less morphine use. In another multicenter, randomized, controlled study, sickle cell crisis was reduced up to 25% in patients given iNO via face mask for 8 hours and via nasal cannula for up to 72 hours.²⁴
If a technology were developed to allow a physician to stimulate the descending corticospinal tracts that result in endogenous morphine release, many of the problems that occur with administration of exogenous opioids would be prevented, namely physical dependence. So far, this has been accomplished using OMT, although the exact mechanisms are currently being studied. Additionally, the use of nitroglycerin transdermal patches can be used to boost morphine efficacy, allowing physicians to administer lower doses of opioids.²⁷ It has been suggested that naloxone be administered to patients suffering from conditions of excess endogenous morphine, such as fibromyalgia or psychoses. Likewise, it has been suggested that subanalgesic doses of morphine be prescribed to patients suffering from conditions that lack endogenous morphine, such as PTSD, pain, and depression.¹ With additional research continuing to uncover the various functions and dysfunctions of endogenous morphine, many idiopathic chronic conditions associated with pain could be safely and effectively treated.