Nicotine, Arthritis and Pain: The Research

Table of Contents

1. Research at a Glance
2. The Papers
3. PubMed Topic Searches
4. More Nicotine Research
5. Connections
6. Featured Videos

Research at a Glance

What kind of study each paper on this page is, and when the papers were published. Hover over a bar for its count.

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The Papers (38)

Newest first. Study types on this page — Human trial: 1 · Human observational study: 1 · Meta-analysis: 1 · Review: 8 · Animal study: 23 · Cell study: 4. Each summary is written from the paper’s own abstract; follow the PubMed link for the full record.

Chronic nicotine exposure elicits pain hypersensitivity through activation of dopaminergic projections to anterior cingulate cortex

Animal study, 2024. In mice, 28 days of nicotine exposure caused increased pain sensitivity to touch that would not normally hurt, measured with fine filaments. The researchers found this happened because nicotine activated a brain pathway carrying dopamine from one region to another (the anterior cingulate cortex), and blocking that pathway, or blocking a specific dopamine receptor in that area, reduced the nicotine-induced pain sensitivity.

Chen D, Shen L, Zhang YZ et al. (2024). Chronic nicotine exposure elicits pain hypersensitivity through activation of dopaminergic projections to anterior cingulate cortex. Br J Anaesth. — PubMed PMID: 38336518 · doi:10.1016/j.bja.2023.12.034

Pharmacological characterization of 5-iodo-A-85380, a β2-selective nicotinic receptor agonist, in mice

Animal study, 2022. Researchers tested a nicotine-receptor drug called 5-iodo-A-85380, which specifically activates the β2 part of nicotinic receptors, in mice. The drug caused lowered body temperature, reduced movement, and pain relief in one pain test (a chemical irritant test) but not in two others (a hot-plate or tail-flick heat test); mice also showed a preference for a place associated with the drug. These effects depended on the β2 receptor subunit, not the α6 subunit, and the drug strongly activated one form of the α4β2 receptor while only partially activating another form and other related receptor types.

Akinola LS, Bagdas D, Alkhlaif Y et al. (2022). Pharmacological characterization of 5-iodo-A-85380, a β2-selective nicotinic receptor agonist, in mice. J Psychopharmacol. — PubMed PMID: 36321267 · doi:10.1177/02698811221132214

Anti-inflammatory activity of nicotine isolated from Brassica oleracea in rheumatoid arthritis

Cell study, 2022. Researchers extracted and purified nicotine from a vegetable (Brassica oleracea) and tested it on human synovial cells grown in the lab that had been triggered to become inflamed, mimicking rheumatoid arthritis. At a low concentration (1 microgram/ml), nicotine reduced the activity of several inflammatory genes and proteins (TNF, IL6, IL1β, TRAF2, P50, P65) in these cells. Computer modeling was also used to study nicotine's drug-like properties. This is a lab dish (cell) study only, not a test in animals or people.

Rakhecha B, Agnihotri P, Dakal TC et al. (2022). Anti-inflammatory activity of nicotine isolated from Brassica oleracea in rheumatoid arthritis. Biosci Rep. — PubMed PMID: 35289351 · doi:10.1042/BSR20211392

Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects

Review, 2022. This review looks at how nicotine affects inflammation across a range of diseases, including inflammatory bowel disease, arthritis, multiple sclerosis, sepsis, and oral inflammation. Drawing on studies from the past 20 years, the authors report that nicotine is mostly anti-inflammatory, especially in ulcerative colitis, arthritis, sepsis, and endotoxemia, but it can worsen oral conditions like periodontitis and gingivitis. The paper also summarizes dosage ranges and possible mechanisms, such as effects on immune cells and the vagus nerve/acetylcholine pathway.

Zhang W, Lin H, Zou M et al. (2022). Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects. Front Immunol. — PubMed PMID: 35251010 · doi:10.3389/fimmu.2022.826889

Nicotine-induced C-shape movements in planarians are reduced by antinociceptive drugs: Implications for pain in planarian paroxysm etiology?

Animal study, 2022. Researchers studied planarians (flatworms) and found that nicotine caused dose-dependent C-shape body contortions. These nicotine-induced movements were reduced by three different pain-relieving drug types tested on the worms: an opioid agonist, an anti-inflammatory drug (meloxicam), and a TRPA1 channel blocker, as well as by a muscle-blocking drug. The opioid drug's effect was reversed by naloxone, an opioid-blocker, suggesting an opioid-receptor mechanism. The findings suggest the nicotine-triggered movements may reflect a pain response in these worms.

Kim A, Rawls SM (2022). Nicotine-induced C-shape movements in planarians are reduced by antinociceptive drugs: Implications for pain in planarian paroxysm etiology?. Brain Res. — PubMed PMID: 34979130 · doi:10.1016/j.brainres.2021.147770

Linalyl acetate as a potential preventive agent against muscle wasting in rheumatoid arthritis rats chronically exposed to nicotine

Animal study, 2021. This study was done in rats with an arthritis similar to rheumatoid arthritis, not in people. Some of the rats were also given nicotine for 22 days. Rats given both arthritis and nicotine had worse muscle wasting than rats with arthritis alone: their calf muscle was lighter, the muscle fibres were thinner, and the muscle's energy-producing parts (mitochondria) changed. Lavender oil, or its main ingredient linalyl acetate, given twice a week prevented these changes in the rats, and linalyl acetate did better than lavender oil at stopping the drop in a growth hormone called IGF-1.

Seo E, Shin YK, Hsieh YS et al. (2021). Linalyl acetate as a potential preventive agent against muscle wasting in rheumatoid arthritis rats chronically exposed to nicotine. J Pharmacol Sci. — PubMed PMID: 34294369 · doi:10.1016/j.jphs.2021.05.003

Bufotenine and its derivatives: synthesis, analgesic effects identification and computational target prediction

Animal study, 2021. Researchers made a chemical derivative of bufotenine, a compound from toad venom, and tested its pain-relieving effects in mice with formalin-induced pain. The derivative reduced pain behavior, and combining it with morphine gave a stronger effect than either alone. Computer modeling of 36 pain-related targets suggested the compound and its relatives work mainly through acetylcholinesterase and the nicotinic acetylcholine receptor subtype known as alpha4beta2.

Zhao C, Chen M, Sun SL et al. (2021). Bufotenine and its derivatives: synthesis, analgesic effects identification and computational target prediction. Chin J Nat Med. — PubMed PMID: 34092296 · doi:10.1016/S1875-5364(21)60044-4

The role of α7-nicotinic acetylcholine receptor in a rat model of chronic nicotine-induced mechanical hypersensitivity

Animal study, 2021. Researchers gave rats nicotine over a long period to study why smokers have more chronic pain than non-smokers. Long-term nicotine made the rats more sensitive to touch, lowering the point at which they reacted to pressure as painful. It also raised levels of one type of nicotinic receptor (the alpha-7 receptor) in a pain-control area of the brain and lowered it in the spinal cord, and it increased immune cells called microglia and the inflammatory signals TNF-alpha and COX-2 in the spinal cord, while a single dose of a drug that activates the alpha-7 receptor reversed the extra sensitivity. The authors suggest that less alpha-7 receptor in the spinal cord and more nerve-immune activity there may help cause chronic pain, but these results are only in rats.

Zhang Y, Sevilla A, Weller R et al. (2021). The role of α7-nicotinic acetylcholine receptor in a rat model of chronic nicotine-induced mechanical hypersensitivity. Neurosci Lett. — PubMed PMID: 33352289 · doi:10.1016/j.neulet.2020.135566

Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8+ T Cells in Rheumatoid Arthritis

Human observational study, 2020. Researchers looked at CD8+ T cells, a type of immune cell, in blood from smokers and non-smokers, both with and without rheumatoid arthritis. Smokers had more of a 'naïve-memory' type of CD8+ T cell, which carries low levels of PD-1, an immune 'brake' protein. These cells also showed a different pattern of eight microRNAs, small molecules that control which genes are switched on, and these microRNAs are predicted to act on the FOXO pathway, which shapes immune memory. When the researchers exposed the cells to nicotine in the lab, two of these microRNAs went up and the balance in the FOXO pathway reversed. The nicotine part of the study was done only on cells in a dish.

Wasén C, Ospelt C, Camponeschi A et al. (2020). Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8+ T Cells in Rheumatoid Arthritis. Front Immunol. — PubMed PMID: 32765511 · doi:10.3389/fimmu.2020.01474

Review: The nicotinic modulation of pain

Review, 2020. This review discusses how nicotinic receptors in the body help control pain signals. It explains that several receptor subtypes, especially alpha7, alpha4beta2, and alpha9alpha10, are involved in different pain processes, and that turning some of these receptors on (agonism) or others off (antagonism) could help with pain. The review notes that drugs targeting these receptors have historically caused side effects, but says clinical developments have been reducing them, and mentions that compounds which boost the effect of these receptor-targeting drugs are also being explored.

Bektas N, Nemutlu D, Cam M et al. (2020). Review: The nicotinic modulation of pain. Pak J Pharm Sci. — PubMed PMID: 32122853

Prenatal nicotine exposure increases osteoarthritis susceptibility in male elderly offspring rats via low-function programming of the TGFβ signaling pathway

Animal study, 2019. This study in rats looked at whether exposing pregnant rats to nicotine affects the knee joints of their male offspring later in life. The offspring were fed a high-fat diet for 6 months and made to run long distances for 6 weeks. At 18 months of age, the offspring exposed to nicotine before birth had more cartilage damage and faster-progressing osteoarthritis, with higher levels of inflammation markers, cartilage-breakdown enzymes and cell-death factors, and lower activity of a cartilage-protecting signaling pathway called TGFβ. Before birth, these offspring already had fewer cartilage cells and less cartilage matrix. These results come from rats only.

Chen B, Lu KH, Ni QB et al. (2019). Prenatal nicotine exposure increases osteoarthritis susceptibility in male elderly offspring rats via low-function programming of the TGFβ signaling pathway. Toxicol Lett. — PubMed PMID: 31299270 · doi:10.1016/j.toxlet.2019.06.010

Estrogen reverses nicotine-induced inflammation in chondrocytes via reducing the degradation of ECM

Cell study, 2019. Researchers looked at how nicotine and the female hormone estrogen together affect cartilage cells, to understand how smoking might relate to osteoarthritis in women. They added nicotine to immune cells called macrophages, collected the inflammatory fluid those cells made, and put it on cartilage cells. That fluid broke down the cartilage's supporting material, including type II collagen, aggrecan and proteoglycan 4. Estrogen at normal body levels (1 nmol/L) reversed this damage, mainly by blocking the enzymes that break down cartilage; these results come from cells in a dish, not from people.

Peng X, Qiao Z, Wang Y et al. (2019). Estrogen reverses nicotine-induced inflammation in chondrocytes via reducing the degradation of ECM. Int J Rheum Dis. — PubMed PMID: 30746895 · doi:10.1111/1756-185X.13476

Antinociceptive effects of novel epibatidine analogs through activation of α4β2 nicotinic receptors

Animal study, 2018. Researchers tested new lab-made compounds related to epibatidine that activate a4β2 nicotinic receptors, the same receptor type nicotine acts on. In mice, three of the compounds reduced pain responses from a formalin injection, with one (C-9515) having the strongest painkilling effect, and this effect was blocked by a drug that blocks nicotinic receptors. The same compound also reduced long-term nerve pain in rats after a nerve injury, an effect blocked specifically by an a4β2 receptor blocker, showing the pain relief worked through this nicotinic receptor pathway.

Li W, Cai J, Wang BH et al. (2018). Antinociceptive effects of novel epibatidine analogs through activation of α4β2 nicotinic receptors. Sci China Life Sci. — PubMed PMID: 29435707 · doi:10.1007/s11427-017-9062-3

Nicotinic modulation of descending pain control circuitry

Animal study, 2017. Researchers studied nicotinic receptors, the brain receptors that nicotine acts on, in a pain-control pathway running from the midbrain to the brainstem. They used brain slices from adult male rats and found that 63% of the nerve cells in this pathway had working nicotinic receptors, all of the alpha-7 type, and these were mostly different cells from the ones carrying opioid receptors. In rats, a lab drug that switches on only alpha-7 receptors reduced pain responses in a formalin pain test, whether it was given by injection into the body or directly into this brain area. Blocking alpha-7 receptors in that brain area stopped the effect, and lower doses of the drug combined with morphine added together to reduce pain. These results come from rats only.

Umana IC, Daniele CA, Miller BA et al. (2017). Nicotinic modulation of descending pain control circuitry. Pain. — PubMed PMID: 28817416 · doi:10.1097/j.pain.0000000000000993

Effect of nicotine on the proliferation and chondrogenic differentiation of the human Wharton's jelly mesenchymal stem cells

Cell study, 2017. Researchers grew human stem cells from umbilical cord tissue (Wharton's jelly) in the lab and exposed them to nicotine at 5 μM, to see whether it affected their growth and their ability to turn into cartilage cells. From the third day of treatment, nicotine significantly slowed the cells' growth, but it did not significantly reduce their survival. Nicotine-treated cells made less proteoglycan, a key cartilage material, and showed lower activity of the cartilage genes Sox9, type II collagen and aggrecan; total collagen did not differ. The cells carried α7 nicotinic receptors, and nicotine caused calcium to flow into them, so the authors suggest these receptors probably drive the harmful effect. These results are from cells in a dish only.

Yang X, Qi Y, Avercenc-Leger L et al. (2017). Effect of nicotine on the proliferation and chondrogenic differentiation of the human Wharton's jelly mesenchymal stem cells. Biomed Mater Eng. — PubMed PMID: 28372298 · doi:10.3233/BME-171644

Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis

Animal study, 2017. Researchers looked at neutrophil extracellular traps (NETs), which are web-like strands of DNA that a type of white blood cell called a neutrophil throws out. They studied this in blood cells from smokers and non-smokers, and in mice with a lab model of rheumatoid arthritis. Neutrophils from smokers formed more NETs. When nicotine was added in the lab to neutrophils from healthy non-smokers, they formed more NETs as the dose went up, and this worked through the alpha-7 nicotinic receptor on those cells. In the mice, nicotine made the arthritis worse and raised blood markers of NETs, so the authors suggest that nicotine-containing products, including e-cigarettes, may be harmful for people with rheumatoid arthritis.

Lee J, Luria A, Rhodes C et al. (2017). Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis. Rheumatology (Oxford). — PubMed PMID: 28013195 · doi:10.1093/rheumatology/kew449

Nicotine Deprivation Produces Deficits in Pain Perception that are Moderately Attenuated by Caffeine Consumption

Human trial, 2016. This controlled study tested pain sensitivity in smokers and non-smokers. Researchers used a heat stimulus to measure pain threshold and pain tolerance before and 30 minutes after the participants drank coffee. When smokers went 2 hours without nicotine, their pain threshold went up and their pain tolerance went down, a pattern the authors describe as heightened pain sensitivity (hyperalgesia). In nicotine-deprived smokers, caffeine brought the raised pain threshold back toward the level seen in non-smokers but had no effect on pain tolerance.

Baiamonte BA, Stickley SC, Ford SJ (2016). Nicotine Deprivation Produces Deficits in Pain Perception that are Moderately Attenuated by Caffeine Consumption. J Psychoactive Drugs. — PubMed PMID: 27120004 · doi:10.1080/02791072.2016.1172745

Acute analgesic effects of nicotine and tobacco in humans: a meta-analysis

Meta-analysis, 2016. This meta-analysis pooled 13 published human laboratory studies (21 tests of pain tolerance covering 393 people, and 15 tests of pain threshold covering 339 people) to see whether nicotine, given through tobacco smoke or through other forms such as a patch or nasal spray, changes how people respond to experimental pain. Overall, nicotine produced a short-term pain-dulling effect that the authors describe as small to medium (Hedges g = 0.35), and after correcting for publication bias the effect was still significant but probably closer to small. The effect on pain threshold was stronger in study groups that included more men than women. The authors note that this short-term pain relief could make smoking more rewarding and harder to quit, and that it may help inform the treatment of both pain and nicotine dependence.

Ditre JW, Heckman BW, Zale EL et al. (2016). Acute analgesic effects of nicotine and tobacco in humans: a meta-analysis. Pain. — PubMed PMID: 27023418 · doi:10.1097/j.pain.0000000000000572

Allosteric Modulation of Nicotinic Acetylcholine Receptors: The Concept and Therapeutic Trends

Review, 2016. This review discusses nicotinic acetylcholine receptors, the molecular targets that nicotine acts on, and a class of drugs called positive allosteric modulators that can boost the activity of these receptors. The paper explains that turning on these receptors has been linked to protecting brain cells from injury, improving attention and thinking, and producing anti-inflammatory and pain-relieving effects in mammals. It reviews the concept of allosteric modulation and current approaches to developing drugs that target these receptors therapeutically.

Uteshev VV (2016). Allosteric Modulation of Nicotinic Acetylcholine Receptors: The Concept and Therapeutic Trends. Curr Pharm Des. — PubMed PMID: 26831463 · doi:10.2174/1381612822666160201115341

Secretome analysis of human articular chondrocytes unravels catabolic effects of nicotine on the joint

Cell study, 2016. Researchers tested nicotine on cartilage cells taken from human knee joints and grown in the lab. Some cells were treated with an inflammatory signal (interleukin-1 beta) to mimic an inflamed joint, and others came from people with osteoarthritis. In the inflamed-joint model, nicotine changed the levels of nineteen proteins the cells released, including several inflammation signals and enzymes that break down tissue. It raised the release of a cartilage-degrading enzyme (matrix metalloproteinase 1) and two suggested markers of osteoarthritis, and it lowered four building blocks of cartilage in the osteoarthritis cells, which the authors read as a harmful effect of nicotine on the joint; these results come from cells in a dish only.

Lourido L, Calamia V, Fernández-Puente P et al. (2016). Secretome analysis of human articular chondrocytes unravels catabolic effects of nicotine on the joint. Proteomics Clin Appl. — PubMed PMID: 25914226 · doi:10.1002/prca.201400186

Effects of nicotine on a rat model of early stage osteoarthritis

Animal study, 2015. Researchers tested nicotine in adult male rats with early-stage osteoarthritis, which they caused by keeping the left knee joint immobilized for two weeks. The rats were then given nicotine in their feed for two or four weeks, and the knee cartilage was checked by eye, under the microscope and with high-field MRI. Nicotine reduced cartilage destruction and helped the cartilage produce more of its supporting matrix. It also lowered an inflammatory signal called TNF-alpha in the blood and in the joint lining, and raised levels of a nicotinic receptor (alpha7) in the joint lining. These results come only from rats, and the authors suggest nicotine may have potential as a treatment for early-stage osteoarthritis.

Gu Q, Li D, Wei B et al. (2015). Effects of nicotine on a rat model of early stage osteoarthritis. Int J Clin Exp Pathol. — PubMed PMID: 26097542

Smoking and osteoarthritis: a review of the evidence and its implications

Review, 2015. This is a review and editorial discussing studies suggesting that smokers have less osteoarthritis than nonsmokers. It examines possible mechanisms by which nicotine might affect joint disease, and also looks at smoking's link to increased musculoskeletal pain and its protective association with ulcerative colitis and Parkinson's disease.

Felson DT, Zhang Y (2015). Smoking and osteoarthritis: a review of the evidence and its implications. Osteoarthritis Cartilage. — PubMed PMID: 25454371 · doi:10.1016/j.joca.2014.11.022

Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2'-fluoro-3'-(substituted pyridinyl)-7-deschloroepibatidine analogues

Animal study, 2014. Researchers created new chemical variants related to epibatidine (a nicotine-like compound) and tested how well they bound to nicotinic receptors and how they behaved in mice. Some of these lab-made compounds acted like nicotine itself (activating the receptors), while a couple of them actually blocked nicotine's pain-related effects in specific pain tests (tail-flick and hot-plate) in mice. This is basic chemistry and animal-testing work, not a study in people.

Ondachi PW, Castro AH, Bartkowiak JM et al. (2014). Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2'-fluoro-3'-(substituted pyridinyl)-7-deschloroepibatidine analogues. J Med Chem. — PubMed PMID: 24428686 · doi:10.1021/jm401602p

Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases

Review, 2011. This review discusses how a receptor that nicotine acts on, called the alpha7 nicotinic receptor, may help calm harmful inflammation linked to diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis. It describes earlier preclinical studies (not in humans) suggesting that activating this receptor on immune cells can reduce inflammatory signaling molecules called cytokines. The authors suggest that if these findings hold up in people, this receptor pathway could become a new way to treat several inflammatory conditions, but say human effectiveness is not yet established.

Bencherif M, Lippiello PM, Lucas R et al. (2011). Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol Life Sci. — PubMed PMID: 20953658 · doi:10.1007/s00018-010-0525-1

Smoking and pain: pathophysiology and clinical implications

Review, 2010. This review looks at how smoking and nicotine affect pain, since cigarette smoke is the main way people get nicotine. Lab studies suggested nicotine can reduce pain, but studies looking at smokers in the real world found that smoking is actually linked to a higher risk of chronic pain. The review covers how nicotine and nicotinic receptors work, why smoking and chronic pain conditions are connected, and what this might mean for doctors treating pain in smokers.

Shi Y, Weingarten TN, Mantilla CB et al. (2010). Smoking and pain: pathophysiology and clinical implications. Anesthesiology. — PubMed PMID: 20864835 · doi:10.1097/ALN.0b013e3181ebdaf9

Alpha9 nicotinic acetylcholine receptors and the treatment of pain

Review, 2009. This review discusses small peptide compounds derived from marine cone snails that block a specific type of nicotinic receptor (the alpha9alpha10 receptor), a receptor that nicotine itself also acts on. These peptides had been shown in earlier studies to relieve pain and help nerve recovery after injury. In the laboratory testing done for this paper, the researchers could not confirm an earlier report that these peptides also act on a different receptor (GABA-B) in human cells and frog egg cells.

McIntosh JM, Absalom N, Chebib M et al. (2009). Alpha9 nicotinic acetylcholine receptors and the treatment of pain. Biochem Pharmacol. — PubMed PMID: 19477168 · doi:10.1016/j.bcp.2009.05.020

Evidence for the tonic inhibition of spinal pain by nicotinic cholinergic transmission through primary afferents

Animal study, 2007. This mouse study looked at whether nerve cells that carry signals from the body to the spinal cord use acetylcholine, a chemical messenger that acts on nicotinic receptors, to keep pain signals turned down all the time. When the researchers blocked the enzyme these nerve cells use to make acetylcholine, the mice became more sensitive to pressure, heat and electrical stimulation of their paws. A single dose of nicotine (10 nmol) given into the spinal fluid brought their pain thresholds back up, but it had no effect on pain thresholds in normal mice. The results come from mice only and have not been tested in people.

Matsumoto M, Xie W, Inoue M et al. (2007). Evidence for the tonic inhibition of spinal pain by nicotinic cholinergic transmission through primary afferents. Mol Pain. — PubMed PMID: 18088441 · doi:10.1186/1744-8069-3-41

Antinociceptive effect of nicotine in various pain models in the mouse

Animal study, 2005. Researchers injected nicotine directly into the brain or spinal fluid of mice and tested its effect on pain in several models, including a chemical irritant test and an acid-induced pain test. Nicotine reduced pain behavior in a dose-dependent way in these mouse tests, and injecting it into the brain appeared more effective at reducing pain than injecting it into the spinal fluid.

Han KJ, Choi SS, Lee JY et al. (2005). Antinociceptive effect of nicotine in various pain models in the mouse. Arch Pharm Res. — PubMed PMID: 15789753 · doi:10.1007/BF02977717

Neuronal nicotinic receptor subtypes: defining therapeutic targets

Review, 2004. This review discusses nicotinic acetylcholine receptors in the brain and argues that, despite the long history of tobacco use for effects like alertness, reduced anxiety, muscle relaxation, and pain relief, the therapeutic potential of nicotine's central nervous system actions has only been seriously studied for less than two decades. It notes that drugs targeting these cholinergic systems have so far been limited mainly to a few niche uses (gut and eye conditions, and muscle-paralyzing drugs used during surgery) because available cholinergic drugs tend to have significant side effects.

Buccafusco JJ (2004). Neuronal nicotinic receptor subtypes: defining therapeutic targets. Mol Interv. — PubMed PMID: 15471911 · doi:10.1124/mi.4.5.8

Tonic nicotinic modulation of serotoninergic transmission in the spinal cord

Animal study, 2001. Researchers studied spinal cord tissue slices from mice to see how nicotine-type (nicotinic) receptors affect the release of serotonin, a chemical that helps dampen pain signals. They found at least three different populations of these receptors in the spinal cord, each responding differently to the body's own natural acetylcholine, and some being switched on at a steady baseline level. The findings suggest these receptor populations are key targets through which nicotine produces pain-relieving (antinociceptive) effects, and that the body's own acetylcholine normally helps regulate this serotonin pathway.

Cordero-Erausquin M, Changeux JP (2001). Tonic nicotinic modulation of serotoninergic transmission in the spinal cord. Proc Natl Acad Sci U S A. — PubMed PMID: 11226321 · doi:10.1073/pnas.041600698

Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors

Animal study, 1998. Researchers tested new chemical compounds that act on the same nicotinic receptors as nicotine, in mice. Two versions of the compound (called ABT-594 and its mirror-image form) relieved pain in standard mouse pain tests (a hot-plate test and an abdominal-pain test) when given either by injection or by mouth. Compared to a related, highly potent nicotine-receptor painkiller, one form of the new compound caused fewer side effects typical of this drug class, and the researchers identified which parts of its chemical structure were important for its pain-relieving effect.

Holladay MW, Wasicak JT, Lin NH et al. (1998). Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors. J Med Chem. — PubMed PMID: 9484491 · doi:10.1021/jm9706224

Inhibition of bradykinin-induced synovial plasma extravasation produced by intrathecal nicotine is mediated by the hypothalamopituitary adrenal axis

Animal study, 1996. In rats, nicotine given directly into the spinal fluid strongly reduced bradykinin-triggered fluid leakage (plasma extravasation) in the knee joint. Experiments testing different nerve and hormone pathways showed this effect depended on the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptors, since removing the pituitary gland or blocking glucocorticoid receptors largely blocked nicotine's effect, while cutting sympathetic nerves or blocking adrenal epinephrine did not.

Miao FJ, Jänig W, Green PG et al. (1996). Inhibition of bradykinin-induced synovial plasma extravasation produced by intrathecal nicotine is mediated by the hypothalamopituitary adrenal axis. J Neurophysiol. — PubMed PMID: 8930234 · doi:10.1152/jn.1996.76.5.2813

Different methods of assessing nicotine-induced antinociception may engage different neural mechanisms

Animal study, 1995. Rats were given nicotine and tested with two pain-response methods: pulling the tail out of hot water and pulling a paw off a hot plate. Nicotine reduced pain response in both tests, but blocking nicotine receptors outside the brain and spinal cord stopped the tail-withdrawal effect while leaving the paw-withdrawal effect unaffected; a drug that blocks nicotine receptors throughout the body and brain blocked both. The researchers concluded these two pain tests measure effects of nicotine working through at least partly different nerve pathways.

Caggiula AR, Epstein LH, Perkins KA et al. (1995). Different methods of assessing nicotine-induced antinociception may engage different neural mechanisms. Psychopharmacology (Berl). — PubMed PMID: 8748400 · doi:10.1007/BF02246552

Involvement of the serotonergic system in the hypoactive and antinociceptive effects of nicotine in mice

Animal study, 1994. Researchers tested mice to find out how nicotine reduces pain sensitivity (an effect called antinociception) and causes reduced movement (hypomotility). Blocking several serotonin receptor types did not change nicotine's effect on reducing movement. However, two drugs that activate serotonin 5-HT1A receptors reduced nicotine's pain-relieving effect in a dose-dependent way, roughly doubling the amount of nicotine needed to produce the same pain relief. The findings point to serotonin 5-HT1A receptors as playing a role in how nicotine reduces pain in mice.

Damaj MI, Glennon RA, Martin BR (1994). Involvement of the serotonergic system in the hypoactive and antinociceptive effects of nicotine in mice. Brain Res Bull. — PubMed PMID: 8275340 · doi:10.1016/0361-9230(94)90252-6

Adrenal medullary modulation of the inhibition of bradykinin-induced plasma extravasation by intrathecal nicotine

Animal study, 1993. Researchers injected nicotine into the spinal fluid of rats to see if it could reduce fluid leakage (plasma extravasation) in the knee joint triggered by bradykinin, a pain-and-inflammation chemical. Spinal nicotine did reduce this leakage, but only at very high doses, and the effect depended heavily on the adrenal medulla: in rats whose adrenal medulla was removed, a million-times-smaller dose of nicotine produced the same effect. The researchers also found that fluid taken from the joints of nicotine-treated rats could reduce leakage when given to other rats, suggesting nicotine triggers release of some substance from the adrenal medulla that acts locally in the joint; this substance did not appear to work through adrenaline, certain serotonin, or opioid receptors tested.

Miao FJ, Dallman MF, Benowitz NL et al. (1993). Adrenal medullary modulation of the inhibition of bradykinin-induced plasma extravasation by intrathecal nicotine. J Pharmacol Exp Ther. — PubMed PMID: 8094755

Multiple spinal mediators in parenteral nicotine-induced antinociception

Animal study, 1993. Researchers gave male rats nicotine injections under the skin and tested their pain responses using heat-based pain tests (hot plate and tail-flick). Higher doses of nicotine reduced pain sensitivity in a dose-dependent way. Using drugs that block specific nerve-signaling pathways in the spinal cord, the researchers found that nicotine's pain-reducing effect depended on several chemical messenger systems there, including alpha-2 adrenergic, serotonin, and acetylcholine (muscarinic) pathways.

Rogers DT, Iwamoto ET (1993). Multiple spinal mediators in parenteral nicotine-induced antinociception. J Pharmacol Exp Ther. — PubMed PMID: 7901397

Modulation of nicotine-induced analgesia by calcium agonist and antagonist in adult rats

Animal study, 1993. This study in adult male rats looked at how calcium affects nicotine's pain-blocking effect, measured by how long the rats took to flick their tails away from heat. A single nicotine injection had its strongest effect within 8-10 minutes and that peak lasted 4 minutes. Rats first given EDTA, a chemical that binds calcium, felt the effect sooner (within 2 minutes) and for longer (10-20 minutes), while rats first given extra calcium had a weaker effect. The authors suggest nicotine may block pain by changing how calcium moves across nerve cell membranes, but this was shown only in rats.

Chin CW, Block RC, Wu WH et al. (1993). Modulation of nicotine-induced analgesia by calcium agonist and antagonist in adult rats. Psychopharmacology (Berl). — PubMed PMID: 7870921 · doi:10.1007/BF02244658

Involvement of calcium and L-type channels in nicotine-induced antinociception

Animal study, 1993. Researchers gave mice nicotine along with drugs that raise or lower calcium inside spinal nerve cells, then tested pain relief. Drugs that increased intracellular calcium made nicotine's pain-blocking effect stronger, while drugs that decreased calcium blocked it. Drugs that block a specific type of calcium channel (L-type) also blocked nicotine's pain-relieving effect, though nicotine itself did not bind to the usual test site for that channel. A nicotine-blocking drug (mecamylamine) stopped the pain relief caused by the calcium-raising drugs too, suggesting these calcium pathways are linked to nicotine's nicotinic receptor activity in the spinal cord.

Damaj MI, Welch SP, Martin BR (1993). Involvement of calcium and L-type channels in nicotine-induced antinociception. J Pharmacol Exp Ther. — PubMed PMID: 7690401

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1. PubMed: Arthritis and Pain and nicotine (the search this page is built from)

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Connections

• How a Joint Works and What Goes Wrong in Arthritis — interactive animation
• Pain, the Gate Control & Why Rubbing Helps — interactive animation
• Nicotine: The Research
• Dr. Bryan Ardis on this subject — his claims, presented on their own pages and kept separate from this research collection
• The Nicotine Patch, animated
• Nicotinic Acetylcholine Receptors
• Cigarette Smoke — what burnt tobacco adds that nicotine alone does not
• Brain and Memory
• Mood and Mental Health
• Inflammation and Immunity
• Cancer Research
• Heart and Blood Vessels
• Metabolism and Weight
• Addiction and Withdrawal
• Patches, Gum and Delivery

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