As acupuncturists of the modern day, most of us have had at least some exposure to the idea of neurotransmitters and the various roles they play in acupuncture mechanisms. If we don't know exactly what they are, we've probably heard them mentioned in research articles or blurbs about electroacupuncture. Some practitioners attempt to bridge the gap to this complex land of elaborately labelled species of substances by finding more simplistic TCM equivalents such as comparing Yin and Yang to oxytocin and cortisol, for example. Love them or shun them, they are here to stay. Neurotransmitters are a fact of human physiology whether you see them as a manifestation of Qi or not.
In fact when we pose a potential parallel between the TCM theory of Qi as a substantial force within human physiology to that of a biochemical mechanism, neurotransmitters would in fact provide quite an accurate comparison. The sheer microcosmic scale upon which these substances operate is akin to the steam that rises from the rice in the poetic explanation of the nature of Qi, and I would say that if we are searching for a scientific contrast, then physiological processes at the molecular level and below are a good place to start.
I thought I would provide a brief as possible synopsis about neurotransmitters and their relevance to acupuncture along with some resources that you can follow down the rabbit hole if you so choose. With such important roles in human physiology, it is not a bad idea to at least get acquainted on a first name basis with some of the more influential members of the endogenous molecular entourage. The full list of neurotransmitters, the actions and relevance to acupuncture could literally fill a book so I have attempted to delivery a truncated summary of some of the more well-known and most influential of the list.
First things first - what exactly is a neurotransmitter?
Neurotransmitters are endogenous chemical substances that enable the transfer of signals via synaptic transmission and neurotransmission (4). These transmission signals alter the electrical properties of target cells in the body in order to generate a variety of physiological effects (1). Communication between neurons is made possible by the transmission of neurotransmitters across synaptic junctions where the axon terminal of the transmitting neuron synapses with the receptive region of the receiving neuron (2:10). Synaptic junctions form the basis of communication throughout the body from axon to dendrite; axon to nerve cell body; even axon to axon (2:10-11), as well as axon to motor end plate which allows for muscle contraction (2:28).
Some neurotransmitters such as oxytocin and vasopressin can also act as hormones (1). A distinctive difference between hormones and neurotransmitters is that hormones typically affect a target cell some distance away from the secreting cell by the release of hormones into the bloodstream (1). Neurotransmitters however usually only travel a distance of from one, to tens or hundreds of micrometers to exert their effect on neighbouring structures (1). Most synaptic sites involve chemical communication in the form of neurotransmitters to transmit impulses, while at other sites, an electrical current passes directly from cell to cell via electrical synapses known as gap junctions (2:11). Electrical signalling also forms the basis of signal propagation by way of action potentials (2:19).
Acetylcholine (ACh)
Acetylcholine acts as a transmitter for a number of functions at a variety of sites throughout the body (2:30). It is responsible for the stimulation of skeletal muscles, muscles of the gastrointestinal tract and vital organs (4). It plays a vital role in normal muscle function as well as scheduling the dream state during sleep (4). Plant poisons such as curare and hemlock cause muscle paralysis by blocking acetylcholine receptors, whereas botulinum, used in botox, prevents the release of ACh in the axon vesicles, in turn resulting in paralysis of the effector muscle (4). Decreased levels of acetylcholine have been found in patients with Alzheimer’s disease (3).
Relevance to Acupuncture
Studies in rats have found that ACh may play a crucial role in the mechanism of acupuncture. It was found that the effectiveness of acupuncture was directly influenced when particular chemicals were introduced into the system that either reduced or increased the levels of ACh (5:129). EA analgesia could be enhanced by subcutaneous injection of neostigmine - a cholinesterase inhibitor that prevents the breakdown of ACh, while EA analgesia was markedly decreased by intraperitoneal injection of hemicholine - an ACh synthesis inhibitor (5:129). This implies that the presence of ACh within the system improves the outcome of an acupuncture treatment.
Amino Acids
Gamma-Aminobutyric Acid (GABA)
GABA is an amino acid derived from glutamate and is the major inhibitory (calming) neurotransmitter in the brain (3). Neuroactive drugs such as benzodiazepines, barbiturates, picrotoxin (poisonous plant compound), and muscimol (primary psychoactive compound of the Amanita muscaria mushroom) all act on GABAA receptors (3). GABAA receptors are also activated by baclofen which acts as a sedative to treat muscles spasm that occur in pathologies such as multiple sclerosis (3). GABA is plays a primary role in reducing neuronal excitability throughout the entire nervous system (4).
Glutamate and Aspartate
These are amino acids that are the major excitatory neurotransmitters in the CNS (3). Glutamate is the most common neurotransmitter in the CNS and helps to ensure homeostasis in combination with GABA (4). It is also responsible for transmitting pain signals in the posterior horn of the spinal cord (2). Glutamate can be toxic at high levels, increasing the occurrence of free radicals, increasing intracellular calcium and proteinase activity (3).
Relevance to Acupuncture
Studies suggest that acupuncture may decrease activity and number of excitatory amino acids in the brain and increase inhibitory amino acids in the CNS (5:130). The reduction of the release of glutamate and aspartic acid via EA was closely associated with significant analgesic effects to ameliorate neuropathic pain (5:131).
Drastically decreased levels of GABA were associated with epilepsy-induced rat models and EA was found to increase the levels of GABA at profound rates of up to 93.6% in the hypothalamus and by 73.7% in the pons (5:131). It is also believed that reduced levels of GABA may be linked to anxiety (4).
Catecholamines
Dopamine
Dopamine has both excitatory and inhibitory effects and is strongly associated with the reward mechanisms in the brain (4). Levels of dopamine in the blood are temporarily increased when the body is exposed to drugs such as alcohol, cocaine, opium and heroin (4). The amino acid L-tyrosine is converted into L-dopa (L-dihydroxyphenylalanine), the precursor to dopamine; dopamine is then transformed into noradrenaline which then in turn becomes adrenaline (6:88)
Noradrenaline (norepinephrine)
Noradrenaline is an excitatory neurotransmitter that increases alertness of the nervous system and stimulate physiological processes (4). Noradrenaline is the precursor molecule to adrenaline (6:88)
Adrenaline - (epinephrine)
Produced by the adrenal glands, adrenaline is an excitatory neurotransmitter that prepares the body for the fight, flight or freeze response (4). When more adrenaline is released into the bloodstream in response to stimulating experiences, heart rate and blood pressure increase along with glycogenolysis (glucose production in the liver) to prepare the body for situation of danger or high intensity (4).
Relevance to Acupuncture
Studies reveal that catecholamines are actively involved in activities in the brain during acupuncture (5:124) and that acupuncture-induced dopamine may alleviate pain synergistically with serotonin and noradrenaline (7). Other research indicates that acupuncture may alter the rate of noradrenaline utilisation and synthesis, ultimately eliciting an analgesia effect by reducing the level of noradrenaline and its metabolite methoxyhydroxyphenylglycol (MHPG) (5:125). It is believed that the presence of beta-endorphin inhibits the activity of noradrenaline during acupuncture (5:126).
Endogenous Opioids
The endogenous opioid system is comprised of three families of neuropeptides called endorphins, enkephalins, and dynorphins which are important mediators of emotional and behavioural responses to stress (9). They are able to inhibit pain sensitive nociceptors and alleviate painful stimuli (6:350).
Beta-Endorphin
Endorphin is a term that refers to an endogenous morphine-like substance that binds to opiate receptors in the brain (2:32). They are able to activate descending, inhibitory axons that run from the brain to the spinal cord and suppress the transmission of pain signals (2:200). The three types of endorphins are alpha, beta and gamma-endorphins (2). Beta-endorphin specifically is involved in pain management with morphine-like effects, as well as the natural reward circuits such as feeding and drinking, sex and maternal behaviour (12). Beta-endorphin has a potency of 18 to 33 times stronger than morphine (11)
Enkephalins (Methionine & Leucine)
Met-enkephalin (methionine) and leu-enkephalin (leucine) are two polypeptide molecules that also bind to opioid receptors in the brain (2:32). Enkephalins are localised in the spinal cord where they modulate pain signals by decreasing the amount of glutamate and substance P (2) - another neurotransmitter that is released in response to intense afferent painful stimuli and modulates the neural response to pain and mood, nausea and vomiting (3). A reduction in substance P therefore attenuates the generation of action potentials and pain perception (2).
Endomorphin (1 & 2)
Endomorphin-1 and endomorphin-2 possess a high affinity and selectivity for the mu-opioid receptor and they play a major role in many physiological processes such as pain perception and stress response, reward and arousal, as well as limbic homeostasis, cognitive, autonomic and neuroendocrine functions (16). From a therapeutic perspective, they may be considered as potent pain relieving and agents (17).
Dynorphin (A & B)
Dynorphin plays an important role in the activity of certain pain circuits in the body (9). It can occur as a result of increased levels of stressed-induced neural activity in response to the release of stress hormones (9). Dynorphin binds with high specificity to its receptor giving it a potency of 200 times stronger than morphine and 50 times more powerful that beta-endorphin (8).
Relevance to Acupuncture
Endogenous opioids play and important role in acupuncture analgesia with elevated plasma levels of beta-endorphin and enkephalin having been observed in human subjects (14:637).
Both met-enkephalin and leu-enkephalin increase markedly in the hypothalamus and corpus striatum in response to acupuncture by acceleration of their biosynthesis (13).
With the advent of EA, treatment responses may now be standardised by the the use of frequency, voltage, waveform and length (14:636). Consequently it has been established that EA at 2 Hz stimulates the release of beta-endorphin, enkephalin and endomorphin within the CNS, while 100Hz stimulates the release of dynorphin (14:637). Maximum therapeutic effect can be obtained by a implementing a combination of these two frequencies as achieved with the dense and disperse function to produce a simultaneous release of all four opioid peptides (15). Not only this, but the intermittent stimulation that occurs in with varying applications of EA reduces the likelihood of tolerance to acupuncture administration and increases the analgesic effect (14:637-638).
Other Important Players...
Oxytocin
Oxytocin is responsible for a variety of crucially important social and reproductive aspects of physiology such as promoting uterine contraction, milk ejection as well as influencing social behaviour (6:394). During late pregnancy, oxytocin receptors form in the uterus aided by an increase in prostaglandin secretion (6:322). During labour, the pressure of the baby pressing on the cervix causes the cervix to stretch which sends signals to the hypothalamus, increasing the release of oxytocin which in turn increases uterine contractions 6:322).
Oxytocin also expels the placenta, constricts uterine vessels and promotes lochial discharge following delivery (6:322). Oxytocic plays a crucial role in preservation of a species in the widest sense as it improves pair bonding behaviour, early maternal bonding and the father’s positive acceptance of his offspring, as well as helping to regulate interpersonal behaviour (6:322). Known as the ‘love hormone’, oxytocin secretion is increased by physical caress while orgasm increases secretion by up to three times (6:322). It has also been shown to be involved in pain modulation within the body (19) as well as stress responses by reducing cortisol levels (21).
Relevance to Acupuncture
Acupuncture has been shown to influence the synthesis and release of oxytocin in both the central and peripheral nervous systems (18). Studies in rat models indicate that acupuncture plays a role in analgesia (19) as well as significantly improving interactive social behaviour (20).
During labour, stimulation of known contraindicated points for pregnancy (BL60, BL67, GB21, LI4, SP9 and SP6) has been found to influence the duration of labour and uterine contractions by stimulating the release of oxytocin (22). SP6 specifically was noted to reduce pain and duration of labour (22).
Interestingly, a 2015 study that reviewed clinical trials involving thousands of participants, it was concluded that there is no reliable evidence that needling contraindicated points during pregnancy causes harm (23). While acupuncture has been shown to stimulate uterine contractions and/ or cervical change, the evidence is not strong enough to conclude that these changes would result in miscarriage or labour, even under favourable circumstances (23).
Serotonin
Serotonin is an inhibitory neurotransmitter involved in mood and emotion (4) and also has vasoconstrictor effects (2:31). It balances excessive excitatory neurotransmitter activity in the brain and a stable mood depends on their being adequate amounts available (4). Serotonin-containing neurons appear to play a role in the experience of sexual arousal, wheil lesions present on these neurons produced insomnia is animal models (2:31). Insufficient amounts of serotonin may be linked to decreased functioning of the immune system, as well as emotion-related disorders including depression, obsessive-compulsive disorder, anger control problems and even suicidal tendencies (4).On this basis, selective serotonin reuptake inhibitors (SSRI’s) are used as a clinical antidepressant as they increase the amount of serotonin available at the postsynaptic membrane (2:31).
Relevance to Acupuncture
Acupuncture has been found to influence the release and enhance the activity of serotonin in the body (5:120) Acupuncture analgesia could be enhanced (24). Acupuncture improves diarrhoea and assist with weight loss in obesity due to its influence over serotonin levels, however a link between serotonin and its ability to ameliorate symptoms of anxiety and depression is still uncertain (24). In rat models, increase in serotonin levels were observed following 20 minutes of acupuncture at BL23 (25). The increased effects lasted for up to 40 minutes with levels returning to baseline at around 120 minutes with bilateral acupuncture causing a greater release of serotonin than unilateral (25).
Image credits: Leah Fehres
References
Purves D., Augustine G. J., Fitzpatrick D., et al., (Eds). (2001). What defines a neurotransmitter?. Neuroscience (2nd Ed.). Viewed 2 February 2021. Source.
Waxman S (2013). Clinical Neuroanatomy (27th Ed.). New York: McGraw Hill.
MSD Manual (2019). Neurotransmission. MSD Manual website. Viewed 2 February 2021, Source.
Kenhub (2021). Neurotransmitters. Kenhub website. Viewed 3 February 2019. Source.
Xia Y., Cao, Xiaoding C., Wu G., Cheng J., (Eds). (2010). Acupuncture Therapy for Neurological Diseases: A neurobiological View. Tsinghuan University Press: Beijing.
Silbernagl S. & Despopoulos A. (2015). Colour Atlas of Physiology (7th Ed.). Stuttgart: Thieme
Zhang R., Lao L., Ren K. & Berman B. (2014). Mechanisms of Acupuncture-Electroacupuncture on Persistent Pain. Anesthesiology. Vol. 120. pp. 482 – 503, viewed 4 February 2021. Source.
Stanford University Medical Centre (1979). Stanford University Medical Centre News Bureau. Stanford Medicine Website. Viewed 4 February 2021. Source.
Knoll A. & Carlezon Jr W. (2009) Dynorphin, Stress, and Depression. Brain Research. Viewed 5 February 2021. Source.
Zhang R., Lao L., Ren K. & Berman B. (2014). Mechanisms of Acupuncture-Electroacupuncture on Persistent Pain. Anesthesiology. Vol. 120. pp. 482 – 503. Viewed 5 February 2021. Source.
Loh H., Tseng L., Wei E. & Li C. (1976) Beta-endorphin is a potent analgesic agent. Proceedings of the National Academy of Sciences of the United States of America. Vol. 73. No. 8. pp. 2895 – 2898. Viewed 5 February 2021. Source.
Sprouse-Blum A., Smith G., Sugai D. & Parsa F. (2010). Understanding Endorphins and Their Importance in Pain Management. Hawaii Medical Journal. Vol. 69. Issue 3. pp. 70 - 71. Viewed 6 February 2021. Source.
Zou G., Yi Q., Wu S., Lu Y., Wang F., Yu Y., Ji X., Zhang Z. & Zhao D. (1980). Enkephalin involvement in acupuncture analgesia-radioimmunoassay. Sci Sin. Viewed 6 February 2021. Source.
Lin J., & Chen W. (2008). Acupuncture Analgesia: A Review of Its Mechanisms of Actions. The American Journal of Chinese Medicine, Vol. 36. No. 4. pp. 635–645. Viewed 8 February 2021. Source.
Han J. (2004). Acupuncture and Endorphins. Neurosci Lett. Viewed 6 February 2021. Source.
Fichna J., Janecka A., Costentin J. & Do Rego J. (2007). The endomorphin system and its evolving neurophysiological role. Pharmacol Rev. 2007 Mar;59(1):88-123. Viewed 6 February 2021. Source.
Horvath G. (200). Endomorphin-1 and endomorphin-2: pharmacology of the selective endogenous mu-opioid receptor agonists. Pharmacol Ther. 2000 88(3). pp. 437 - 63. Viewed 6 February 2021. Source.
Ding S., Hing S., Wang C., Guo Y., Wang Z. & Xu W. (2014). Acupuncture modulates the neuro–endocrine–immune network. QJM: An International Journal of Medicine. Volume 107. Issue 5. pp. 341–345. Viewed 7 February 2021. Source.
Yang J., Yang Y., Chen J., Liu W., Wang C. & Lin B. (2007). Effect of oxytocin on acupuncture analgesia in the rat. Neuropeptides. Vol. 41. Issue 5. Viewed 7 February 2021. Source.
Zhang H., Li H., Dai Y., Xu X., Han S., Zhang R. & Han J. (2015). Electro-acupuncture improves the social interaction behavior of rats. Physiology and Behaviour. Volume 151. pp. 485 - 493. Viewed 7 February 2021. Source.
McQuaid R., McInnis O., Paric A., Al-Yawer F., Matheson K. & Anisman H. (2016). Relations between plasma oxytocin and cortisol: The stress buffering role of social support. Neurobiol Stress. Volume 3. pp. 52 - 60. Viewed 7 February 2021. Source.
Calik K. & Komurcu N. (2014). Effects of SP6 Acupuncture Point Stimulation on Labor Pain and Duration of Labor. Iran Red Crescent Med J. Vol. 16. Issue 10. Viewed 7 February 2021. Source.
Carr D. (2015). The safety of obstetric acupuncture: forbidden points revisited. Acupunct Med. Vol. 35. Issue 5. pp. Viewed 7 February 2021. Source.
Lee E. & Warden S. (2016). The effects of acupuncture on serotonin metabolism. European Journal of Integrative Medicine. Vol. 8. Issue 4. pp. 355-367. Viewed 8 February 2021. Source.
Yoshimoto K., Fukuda F., Hori M., Kato B., Kato H., Hattori H., Tokuda N., Kuriyama K., Yano T. & Yasuhara M. (2006). Acupuncture stimulates the release of serotonin, but not dopamine, in the rat nucleus accumbens. Tohoku J Exp Med. Vol. 208. Issue 4. pp. 321 - 326. Viewed 8 February 2021. Source.