Henry Dale, a British physiologist working in London in 1914, found that two foreign substances, nicotine and muscarine, could each mimic some, but not all, of the parasympathetic effects of acetylcholine. It was found that nicotine stimulates receptors on skeletal muscle and sympathetic and parasympathetic postganglionic neurons. To restate this again, nicotinic receptors cause sympathetic postganglionic neurons and parasympathetic postganglionic neurons to fire and release their chemicals and skeletal muscle to contract.

At the neuromuscular junction, nicotinic acetylcholine receptors are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. Muscles require innervation to function- and even just to maintain muscle tone, avoiding atrophy. In the neuromuscular system, nerves from the central nervous system and the peripheral nervous system are linked and work together with muscles. Synaptic transmission at the neuromuscular junction begins when an action potential reaches the presynaptic terminal of a motor neuron, which activates voltage-gated calcium channels to allow calcium ions to enter the neuron. Calcium ions bind to sensor proteins on synaptic vesicles, triggering vesicle fusion with the cell membrane and subsequent neurotransmitter release from the motor neuron into the synaptic cleft. In vertebrates, motor neurons release acetylcholine, a small molecule neurotransmitter, which diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors on the cell membrane off the muscle fibre.

Neurotransmitters such as acetylcholine and serotonin play crucial roles in brain homeostasis and functioning. Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter - a chemical message released by nerve cells to send signals to other cells, such as neurons, muscle cells and gland cells. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic. Substances that increase or decrease the overall activity of the cholinergic system are called cholinergics and anticholinergics, respectively. These interactions underlie the effects of nicotine on anxiety states observed in smokers and exposed animal models. Among cholinergic receptors, only the nicotinic acetylcholine receptors subtypes are activated directly by nicotine, which is their exogenous ligand present in tobacco smoke. Activation of serotonin receptors by serotonin and that of nicotinic acetylcholine receptors by endogenous acetylcholine or exogenous nicotine result in modulation of a broad range of immunological functions including innate and adaptive immune responses.

Reciprocal interactions between nicotine/acetylcholine and serotonin might occur at vagus nerve and gastrointestinal levels. Nicotine shown to control partly the serotonin transport and content within platelets by distinct cellular mechanisms. One example of such mechanisms is the activation of nicotinic acetylcholine receptors in enterochromaffin cells, which leads to an increase in serotonin concentrations in human platelets. Nicotine also stimulates serotonin release from human blood platelets. These observations provide clear evidence with regard to nicotine serotonin interactions including nicotine’s interference with serotonin effects on immune cells by controlling its availability.

It is interesting that nicotine appears to be beneficial for clinical treatment of ulcerative colitis. Serotonin plays an important role in the regulation of gastrointestinal functions. Serotonin concentrations have shown to decrease in colonic mucosa of individuals suffering from ulcerative colitis and irritable bowel syndrome. In addition to its anti-inflammatory properties, nicotine may therefore prevent the development of such gastrointestinal disorders by increasing the local concentrations of enterochromaffin cells.

The cholinergic anti-inflammatory pathway (CAP) is referred to as the neuroinflammatory reflex in which the nervous and immune systems ‘cooperate’ to control excessive inflammation, and one mechanism by which this occurs is through the activity of the vagus nerve. The vagus nerve is composed of 80% sensory afferent fibers and 20% motor efferent fibers. Vagal nerve fibers innervate the gastrointestinal tract, lungs, heart, pancreas, adrenal glands, and liver and are responsible for the control/modulation of heart rate, digestion, intestinal movement, hormone, and neurotransmitter secretion. The correct function of this nerve is essential for numerous physiological processes of the gut-brain axis. Activation of vagal efferents leads to the release of acetylcholine in visceral organs with the exception of the spleen as this organ is innervated by the splenic nerve, which is adradrenergiche splenic nerve releases noradrenaline and activates adrenergic receptors expressed by a specific subpopulation of resident CD4+ T-cells that are capable of synthesizing and releasing acetylcholine that, in turn, activates resident macrophage expressed α7 nAChRs to inhibit the release of pro-inflammatory cytokines. The anti-inflammatory effects of α7 nAChR activation have been observed through stimulation of enteric macrophages through vagal nerve activity.

Control of inflammation through the CAP has been demonstrated in animal models of human diseases including sepsis, irritable bowel syndrome, arthritis, hemorrhagic shock, asthma, and pancreatitis. In humans, the importance of the role α7 nAChRs play in the CAP and the regulation of exacerbated inflammation has been shown in sterile endotoxemia and sepsis. Activation of the CAP via vagal-nerve stimulation is currently used to treat depression, epilepsy, stroke, and migraines. Vagal-nerve stimulation may also be potentially useful in treating Crohn’s disease, ulcerative colitis, and other inflammatory bowel conditions as has been demonstrated in rodent models of irritable bowel syndrome and postoperative ileus.

Inflammatory bowel disease is a highly prevalent and multifactorial disorder characterized by chronic inflammation of the gastrointestinal tract and significantly affects the quality of life of patients who suffer from it. The two main types are ulcerative colitis, which is limited to the colon, and Crohn’s disease which can affect any section of the intestinal tract. The vagus nerve plays a role in regulating intestinal inflammation in irritable bowel syndrome, and the proposed mechanism involves enteric nervous system neurons and macrophages located in the submucosal plexus. Release of acetylcholine by the vagus nerve contacting enteric nervous system neurons decreases the release of TNF-α, IL-1β, IL-6, and IL-18 by submucosal macrophages expressing α7 nAChRs. In dysbiosis and pathologies such as ulcerative colitis, lymphocytes and macrophages are recruited to the site of inflammation where adhesion molecules are over expressed.

It is well-known that nicotine activates cells through α7nAChR, which is responsible for the activation of cholinergic anti-inflammatory pathway. The presence of α7nAChR on the cell surface of monocytes and macrophages adds to the role of nicotine in the innate immune response. Infections trigger acetylcholine (Ach) release by the vagal nerve, which binds with α7-nAChR on the surface of macrophages and subsequently interferes with the production of pro-inflammatory cytokines. Surprisingly, nicotine has the same effect as that of vagal nerve stimulation, leading to an anti-inflammatory response by shifting the macrophage polarization toward M2, weakening the production of pro-inflammatory cytokines, and increasing the secretion of anti-inflammatory cytokines as well.

Introduction and How to Read the Following Tables

Inflammation plays a pivotal role in the development and progression of countless diseases, ranging from ulcerative colitis and arthritis to obesity, asthma, and periodontitis. Understanding how various compounds — particularly nicotine — influence inflammatory processes is critical for researchers, clinicians, and anyone interested in the intersection of immunology and pharmacology. The tables presented here consolidate a wealth of experimental data from diverse studies that have examined the effects of nicotine across multiple disease models, offering readers a comprehensive overview in one convenient location.

These tables capture essential details from numerous peer-reviewed studies. Each entry typically includes the disease model and species used (for example, mouse models of ulcerative colitis or rat models of arthritis), the specific dosages and methods by which nicotine was administered (oral, subcutaneous, intraperitoneal, or even in vitro applications), and the key inflammatory markers or pathways that were analyzed (such as TNF-α, IL-6, NF-κB, and others). Importantly, they also summarize whether nicotine exhibited a positive anti-inflammatory effect, a less pronounced benefit, or even a pro-inflammatory outcome. Every study is accompanied by its reference — usually a DOI or PMID — so readers can consult the original research for more detailed methodology and findings.

To make the most of these tables, readers are encouraged to start by locating the disease or condition of interest in the first column. From there, they can track across the row to see how nicotine was tested in that context — noting the dosage, route of administration, and the biological factors measured. The “Effect” column provides a quick interpretation of nicotine’s impact, while the reference column allows for deeper exploration of the original data. This structured presentation not only saves time by eliminating the need to comb through individual publications but also enables meaningful comparisons across different studies and disease models.

Ultimately, these tables serve as a valuable resource for gaining insights into the nuanced role of nicotine in inflammation. Whether you are designing new experiments, seeking therapeutic implications, or simply expanding your understanding of nicotine’s complex interactions with inflammatory pathways, this compilation offers a clear starting point backed by robust scientific evidence.