Role of Endogenous Morphine and Nitric Oxide in Pain Management

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.

It has been more than 30 years since morphine was discovered to be an endogenous signal molecule in the body. 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.

Osteopathic manipulative therapy (OMT)has been found to initiate release of nitric oxide (NO), endogenous morphine’s second messenger in the body.

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 acts as a neurotransmitter that readily crosses the blood-brain barrier into the cerebrospinal fluid

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. This exemplifies the second tenet of osteopathic medicine: the body has an innate ability to heal itself.

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. NO is a free radical that diffuses freely through cell membranes. It has the unique property of being the only gas-phase neurotransmitter. 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. 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

What makes pain such a unique sensory experience is its close link to emotional responses.

Endogenous Morphine in Psychiatry

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

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.”

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.

The 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.

Both the MOR and endocannabanoid receptors are coupled with nitric oxide synthase (NOS)

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.

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

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.

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

Vasodilation Action

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 also functions endogenously to activate bradykinin and inhibit platelet aggregation. Bradykinin is a neurotransmitter that causes the sensation of pain.

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. NO may aid in preventing physical dependence because NOS inhibitors have been demonstrated to reduce opioid analgesic tolerance.

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

Related phenomena include the off-label use of iNO for pain of sickle cell crisis.

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

the use of nitroglycerin transdermal patches can be used to boost morphine efficacy, allowing physicians to administer lower doses of opioids.

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.




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  1. Pingback: My EDS Pain | EDS Info (Ehlers-Danlos Syndrome)

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