Morphine's Biopsychology

Morphine is regarded as the typical analgesic against which all different analgesics (painkillers) are measured and compared. There is a lot of evidence that suggests that the drug, an opioid, has been in use for thousands of years in its formerly rudimentary form as an extract of opium poppy. Morphine is one of the four alkaloids that can be derived from P. somniferum, the different three being codeine, thebaine, and papaverine. Opioids are classified based on what they do (their effects) at opioid receptors or the kind of opioid receptor they work at. Based on the former classification, morphine is classified as a pure opioid agonist since it works with a receptor resulting in a maximum response; analgesia (Pathan, & Williams, 2012). The purpose of this paper is to explain the mechanism of action of morphine, including its short term and long term effects, its side effects, and withdrawal effects, if any. In the end a conclusion will be given.

Desired effects

Opioid drugs such as morphine can produce a variety of effects when administered including analgesia, euphoria, decreased consciousness, respiratory depression, tolerance, and physical dependence.

Analgesia

The main effect of morphine is that it reduces pain. Pain is linked to increased activity in the primary sensory neurons. This increased activity is brought about by thermal, or mechanical stimuli, or by chemicals released as a result of inflammation or tissue damage (Chahl, 1996). The primary sensory neurons release glutamate and substance P in the spinal cord’s dorsal horn. This pain information is then transmitted to the brain through the spinothalamic tracts. The information going to the brain can activate descending circuits from the midbrain PAG (Periaqueductal Grey) area (Chahl, 1996).

Opioids such as morphine work by activating receptors on neuronal cell membranes. There are three major types of neuronal cell membrane G protein receptors, namely; k, d, and m (kappa, delta and mu) (Chahl, 1996). These receptors are existent in numerous areas on the nervous system that are involved in pain control and transmission. These areas include; the thalamus, midbrain, primary afferent neurons, and the spinal cord.  

Morphine has high affinity to mu opioid receptor after which it was named. It brings about analgesia by acting mainly in three main ways:

1. It opens voltage-sensitive potassium channels, hyperpolarizing neurons and preventing spike activity (Dafny, n.d.).
2. It closes voltage-gated calcium channels preventing Ca ++ release into the presynaptic terminal blocking neurotransmitter release (Snyder, 2014). Morphine’s action on the mu receptors blocks the release of several different types of neurotransmitters including substance P, neuropeptide, acetylcholine, and noradrenaline.
3. It inhibits adenylate cyclase (Snyder, 2014). All three types of opioid receptors bind to adenylate cyclase which is responsible for the breakdown of ATP (adenosine triphosphate) to cAMP (cylic Adenosine Monophosphate). Morphine binds to this enzyme blocking the release of neurotransmitters.

All these cellular activities will either prevent neurotransmitter release and/ or cutting the transmission of any pain signals. All opioid analgesics including morphine act against the mu receptor (Snyder, 2014). Mu activation blocks the ascending pain pathway, which entails the passing of neurons through the spinal cord’s dorsal horn, the brainstem, thalamus, and finally the cortex. Mu agonists also activate the inhibitory descending pain pathway which involves regions in the brainstem (Snyder, 2014). There are numerous types of opioid receptors distributed in different regions of the peripheral and central nervous systems (Snyder, 2014). This explains the many side effects that result due to morphine treatments.

Side effects

Euphoria

The administration of morphine may also result in euphoria. Euphoria is brought about by the interaction of morphine with the mu opioid receptors. This effect is, however, not dependent on the aforementioned pain pathways. Instead, it is dependent on the effects of morphine on the ventral tegmental region of the brain (Doweiko, 2012). This brain region has numerous dopamine receptor sites that are linked to the limbic system. Narcotic analgesics such as morphine will bind to interneurons, which often inhibit dopamine release in the CNS (Doweiko, 2012). Lack of GABA neuron inhibition will result in the limbic reward system releasing large amounts of dopamine, triggering the brain’s reward system hence the euphoric or exciting sensation (Doweiko, 2012).

Constipation

Almost 90 percent of patients who receive any form of opioid treatment experience constipation. Researchers argue that constipation may be as a result of the interaction of opioids such as morphine with mu opioids receptors in the CNS and ENS. This interaction is thought to stimulate the central nervous system altering the autonomic outflow through it (Babhadiashar et al., 2015). Other researchers put it more simply by contending that constipation as a result of opioid use is multifactorial; i.e. it interferes with gastrointestinal (GIT) motility in several ways resulting in the next effect of constipation (Camilleri, 2011). For instance, it is thought that opioids such as morphine act on enteric neurons stimulating the pyloric sphincter, delaying transit, and stimulating non-propulsive segmentation, tone and motility (Camilleri, 2011). Morphine is also thought to activate the absorption of fluids by delaying transit (increasing contact time for prolonged absorption), and by stimulating mucosal sensory receptors that in turn initiate the reflex arc which promotes more fluid absorption (Camilleri, 2011). All of these actions culminate into OIC (Opioid-Induced Constipation).

Respiratory depression

Perhaps the most dangerous side effect of morphine use is respiratory depression. This is because of the obvious risk of death if the effect is not quickly mitigated or reversed (Dahan, Aarts, & Smith, 2010). Tests done on mice lacking mu-opioid receptors showed that the injection of morphine failed to bring about respiratory depression as opposed to tests done on mice with active mu-opioid receptors (Dahan, Aarts, & Smith, 2010).This led to the conclusion that mu-opioid receptors are the key target for morphine-induced respiratory depression (Dahan, Aarts, & Smith, 2010).

Long term effects

Tolerance

Chronic exposure to morphine results in tolerance and drug dependence (addiction). If an individual develops tolerance it means that he or she requires higher doses of morphine to produce the desired effect. In other words, the previously the prescribed doses do not produce the desired effect; analgesia. Tolerance results from receptor desensitization brought about by opioids receptors unbinding from G proteins (their effector systems) (Chahl, 1996). When morphine binds to an associated G protein receptor, the receptor is activated. This eventually results in a decrease in excitability along neuronal cell membranes in pain pathways resulting in analgesia (Chahl, 1996). Overtime, alterations in this G protein-mediated system may result in uncoupling/ unbinding that could lead to decreased analgesia. Thus, the previously recommended dosage will not alleviate pain. Tolerance and withdrawal may be anticipated from all patients and can be avoided by utilizing a weaning dosage when halting morphine treatment.

Dependence

The effect of dependence, on the other hand, is hidden. It cannot be discovered that one has drug dependence or addiction unless the drug, morphine, is removed from the opioids receptors (Chahl, 1996). This can be done in two ways; by giving an opioid receptor antagonist such as naloxone, or stopping the administration of morphine (Chahl, 1996). A complex withdrawal reaction that affects many brain regions then occurs. Dependence has often been thought to be as a result of increased adenylate cyclase activity after a prolonged period of morphine treatment (Chahl, 1996). 

Withdrawal effects (symptoms)

Recognition impairment

Morphine withdrawal may activate the HPA (hypothalamic pituitary-adrenal) system. Studies show that corticosterone levels increase in the brain from just four hours when the last dose of morphine was administered (Babhadiashar et al., 2015). Corticosterone easily re-enters the brain to interact with glucocorticoid receptors – such as the hippocampal formation – that are involved in memory processes (Campolongo, & Fattore, 2016). An increase in corticosterone levels in the brain explains the recognition impairment (Campolongo, & Fattore, 2016).

Cognitive deficits

Morphine withdrawal activates the body’s endocannabinoid system resulting in cognitive defects (Babhadiashar et al., 2015).

Conclusion

Morphine is one of the most commonly utilized drugs in the treatment of severe or moderate pain. It acts mainly by binding on the mu-opioid receptor bringing about several effects such as; the opening of voltage-sensitive potassium channels, the closing of calcium channels, and the inhibition of adenylate cyclase. These effects prevent the transmission of pain signals resulting in analgesia (pain relief). Despite its amazing analgesic effects morphine is also known to bring about other unintended effects. For instance, quite a number of people misuse the drug because of its euphoric effects. It also has other effects such as constipation, respiratory depression, dependence, tolerance, and many others most of which are mediated or brought about by the interaction of morphine with mu-opioid receptors in various parts of the central and peripheral nervous systems.

References

Babhadiashar, N., Vaseghi, G., Kopaei, M., Andalib, S., Eshraghi, A., & Masoudian, N. (2015). Neural mechanisms underlying morphine withdrawal in addicted patients: a review. Reviews In Clinical Medicine, 2(3). http://dx.doi.org/10.17463/RCM.2015.03.010

Camilleri, M. (2011). Opioid-Induced Constipation: Challenges and Therapeutic Opportunities. The American Journal Of Gastroenterology, 106(5), 835-842. http://dx.doi.org/10.1038/ajg.2011.30

Campolongo, P., & Fattore, L. (2016). Cannabinoid Modulation of Emotion, Memory, and Motivation (1st ed., 37). Springer.

Chahl, L. (1996). Experimental and Clinical Pharmacology: Opioids - mechanisms of action. Australian Prescriber, 19(3), 63-65. http://dx.doi.org/10.18773/austprescr.1996.063

Dafny, N. Pain Modulation and Mechanisms. University of Texas Medical School at Houston. Retrieved 16 May 2017, from http://nba.uth.tmc.edu/neuroscience/s2/chapter08.html

Dahan, A., Aarts, L., & Smith, T. (2010). Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression. Anesthesiology, 112(1), 226-238. http://dx.doi.org/10.1097/aln.0b013e3181c38c25

Doweiko, H. (2012). Concepts of chemical dependency (1st ed., p. 141). Belmont, CA: Brooks/Cole, Cengage Learning.

Pathan, H., & Williams, J. (2012). Basic opioid pharmacology: an update. British Journal Of Pain, 6(1), 11-16. http://dx.doi.org/10.1177/2049463712438493

Snyder, B. (2014). Revisiting old friends: update on opioid pharmacology. Australian Prescriber, 37(2), 56-60. http://dx.doi.org/10.18773/austprescr.2014.021