Nicotine, Arthritis and Pain: The Research

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The Papers (24)

Newest first. Study types on this page — Human observational study: 1 · Review: 1 · Animal study: 19 · Cell study: 3. Each summary is written from the paper’s own abstract; follow the PubMed link for the full record.

Impact of Adolescent Nicotine Exposure in Pre- and Post-natal Oxycodone Exposed Offspring

Animal study, 2023. This animal study looked at what happens when young animals already exposed to the opioid painkiller oxycodone are given rising doses of nicotine during adolescence and then have the nicotine stopped. Some of the animals had been exposed to oxycodone in the womb and others just after birth. The researchers found changes in brain proteins involved in nerve connections, especially higher levels of a protein called synaptophysin in the womb-exposed animals during withdrawal. They also found signs of immune changes in the brain, faster breakdown of nicotine in the womb-exposed animals, and small changes in pain sensitivity and anxiety-like behavior during withdrawal. These results are only in animals.

Flores A, Gowen A, Schaal VL et al. (2023). Impact of Adolescent Nicotine Exposure in Pre- and Post-natal Oxycodone Exposed Offspring. J Neuroimmune Pharmacol. — PubMed PMID: 37351737 · doi:10.1007/s11481-023-10074-x

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

Nicotine withdrawal induces hyperalgesia via downregulation of descending serotonergic pathway in the nucleus raphe magnus

Animal study, 2021. This study used rats to look at why people who stop smoking can become more sensitive to pain, for example around the time of surgery. Rats going through nicotine withdrawal became more sensitive to both pressure and heat, and they had fewer serotonin-making nerve cells in a brainstem area that normally helps turn pain signals down, along with lower serotonin levels in the fluid around the spinal cord. Giving serotonin into the spinal fluid, or boosting serotonin production in that brain area, eased the extra pain sensitivity, while blocking serotonin receptors made it worse. These results are only in rats; the authors suggest they may help improve pain management after surgery for patients who smoke.

Shen L, Qiu HB, Xu HH et al. (2021). Nicotine withdrawal induces hyperalgesia via downregulation of descending serotonergic pathway in the nucleus raphe magnus. Neuropharmacology. — PubMed PMID: 33722649 · doi:10.1016/j.neuropharm.2021.108515

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

Enhancement of Opioid Antinociception by Nicotine

Animal study, 2019. Researchers gave male squirrel monkeys four opioid painkillers (fentanyl, oxycodone, buprenorphine and nalbuphine), each alone and again after a dose of nicotine. They measured pain relief by how long each monkey left its tail in hot water, and side effects by how well it kept pressing a lever to earn milk. Nicotine made every opioid a stronger painkiller: oxycodone became 2 to 7 times more potent, and nalbuphine about 70 times more potent at the lower and middle water temperatures. Nicotine did not worsen the opioids' disruption of the lever-pressing task, and a drug that blocks nicotinic receptors stopped the effect. These results come only from monkeys, and the authors suggest that nicotine might one day let doctors use lower opioid doses for pain.

Barreto de Moura F, Withey SL, Bergman J (2019). Enhancement of Opioid Antinociception by Nicotine. J Pharmacol Exp Ther. — PubMed PMID: 31527281 · doi:10.1124/jpet.119.261438

Nicotine inhibits rapamycin-induced pain through activating mTORC1/S6K/IRS-1-related feedback inhibition loop

Animal study, 2019. Drugs that block a cell-growth signal called mTORC1, such as rapamycin, make pain more common in patients. This study tested whether nicotine could ease that pain, using male mice given rapamycin injections once or repeatedly. Nicotine clearly lowered the mice's extra sensitivity to pain from pressure and heat, reversed rapamycin's effects on several pain-signaling proteins, and calmed nerve-cell firing in a brain area involved in pain (the anterior cingulate cortex); when two types of nicotinic receptor (α4β2 and α7) in that area were blocked, nicotine no longer relieved the pain. These results come from mice only, and the authors suggest pain medicines aimed at these receptors could be developed for patients with rapamycin-related pain.

Li S, Guan S, Wang Y et al. (2019). Nicotine inhibits rapamycin-induced pain through activating mTORC1/S6K/IRS-1-related feedback inhibition loop. Brain Res Bull. — PubMed PMID: 31005665 · doi:10.1016/j.brainresbull.2019.04.016

Nicotine and autoimmunity: The lotus' flower in tobacco

Review, 2018. This review gathers earlier research on how nicotine affects the immune system in autoimmune diseases, including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, sarcoidosis, Behçet's disease and inflammatory bowel diseases. The authors say the findings conflict. Some studies suggest nicotine increases inflammatory signals and makes a type of white blood cell (neutrophils) die and release their contents, which the immune system can then attack as if they were foreign. Other studies suggest nicotine calms inflammation, mainly by binding to the alpha-7 nicotinic receptor, which can increase regulatory T cells and lower inflammatory signals; the authors name addiction and the side effects of each nicotine product sold as the main problems with nicotine.

Gomes JP, Watad A, Shoenfeld Y (2018). Nicotine and autoimmunity: The lotus' flower in tobacco. Pharmacol Res. — PubMed PMID: 29051105 · doi:10.1016/j.phrs.2017.10.005

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

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

Activation of α7 nicotinic acetylcholine receptors prevents monosodium iodoacetate-induced osteoarthritis in rats

Animal study, 2015. This study looked at whether nicotine protects knee joints in rats with chemically induced osteoarthritis, and whether it works through one type of nicotine receptor (the alpha-7 nicotinic receptor). It used live rats and cartilage cells grown in the lab. In the rats, nicotine given into the body reduced damage to the knee joint, and this protection disappeared when a drug that blocks the alpha-7 receptor was also given. In the cartilage cells, nicotine dampened inflammatory signals set off by the damaging chemical or by an inflammatory molecule, and blocking the receptor reversed this too. These results come from rats and lab-grown cells only, not from people.

Liu Y, Wu D, Song F et al. (2015). Activation of α7 nicotinic acetylcholine receptors prevents monosodium iodoacetate-induced osteoarthritis in rats. Cell Physiol Biochem. — PubMed PMID: 25613062 · doi:10.1159/000369724

Nicotine dependence produces hyperalgesia: role of corticotropin-releasing factor-1 receptors (CRF1Rs) in the central amygdala (CeA)

Animal study, 2014. This study used rats made dependent on nicotine by breathing nicotine vapor for 14 hours a day. When the rats were taken off nicotine, they became more sensitive to pain from heat. That extra sensitivity went down when they were given a drug that blocks the receptor for a brain stress signal called corticotropin-releasing factor (CRF), either by injection into the body or straight into a brain area called the central amygdala. The withdrawn rats also had more of the genetic message (mRNA) for CRF and its receptor in that brain area, so the authors suggest that this stress signal drives the extra pain sensitivity during nicotine withdrawal. These results come from rats only.

Baiamonte BA, Valenza M, Roltsch EA et al. (2014). Nicotine dependence produces hyperalgesia: role of corticotropin-releasing factor-1 receptors (CRF1Rs) in the central amygdala (CeA). Neuropharmacology. — PubMed PMID: 24107576 · doi:10.1016/j.neuropharm.2013.09.025

Requirement of the phosphatidylinositol 3-kinase/Akt signaling pathway for the effect of nicotine on interleukin-1beta-induced chondrocyte apoptosis in a rat model of osteoarthritis

Cell study, 2012. Researchers took cartilage cells (chondrocytes) from the joints of newborn rats and grew them in the lab. They exposed the cells to interleukin-1 beta, an inflammatory signal that makes cartilage cells die, as happens in osteoarthritis. Adding nicotine blocked this cell death and helped the cells keep making protein. It did this by switching on a cell-survival pathway called PI3K/Akt, which also changed the levels of TIMP-1 and MMP-13, two proteins involved in cartilage breakdown. These results come only from rat cells in a dish, not from living animals or people.

Zheng X, Xia C, Chen Z et al. (2012). Requirement of the phosphatidylinositol 3-kinase/Akt signaling pathway for the effect of nicotine on interleukin-1beta-induced chondrocyte apoptosis in a rat model of osteoarthritis. Biochem Biophys Res Commun. — PubMed PMID: 22713471 · doi:10.1016/j.bbrc.2012.06.045

Nicotine-induced chondrogenic differentiation of human bone marrow stromal cells in vitro

Cell study, 2012. Researchers treated bone marrow stem cells from three healthy human donors with different concentrations of nicotine in the lab to see how it affected their growth and their ability to turn into cartilage cells. Cell survival was not significantly harmed until the highest concentration tested, and lower concentrations increased cell growth and raised production of type II collagen, a key cartilage protein. At the highest concentration, production of another cartilage component, aggrecan, fell, while genes linked to scar-like and late-stage cartilage changes were reduced at all nicotine levels tested. The authors suggest that nicotine applied locally at the right concentration might help in lab-grown cartilage repair and possibly osteoarthritis, but these results come only from cells in a dish.

Ying X, Zhang W, Cheng S et al. (2012). Nicotine-induced chondrogenic differentiation of human bone marrow stromal cells in vitro. Knee Surg Sports Traumatol Arthrosc. — PubMed PMID: 22258655 · doi:10.1007/s00167-012-1890-0

Smoking and nicotine exposure delay development of collagen-induced arthritis in mice

Animal study, 2009. Researchers studied a mouse model of rheumatoid arthritis. Before arthritis was triggered with an injection of collagen, 25 mice breathed cigarette smoke for 16 weeks, 10 mice got nicotine in their drinking water, and 35 mice served as unexposed controls. Arthritis started later in the smoke-exposed mice, and the nicotine-exposed mice showed similar results. Smoke-exposed mice also had lower levels of two arthritis-related antibodies, and in lab dishes nicotine lowered production of the inflammatory signal IL-6 by stimulated mouse spleen cells. The authors concluded that neither smoke nor nicotine made the arthritis worse in this mouse model, though these results are only in mice and mouse cells.

Lindblad SS, Mydel P, Jonsson IM et al. (2009). Smoking and nicotine exposure delay development of collagen-induced arthritis in mice. Arthritis Res Ther. — PubMed PMID: 19519907 · doi:10.1186/ar2728

Modulatory role of estradiol in nicotinic antinociception in adult female rats

Animal study, 2009. This study was done only in rats. It looked at how the female hormone estradiol affects pain relief produced through nicotinic receptors, the same receptors nicotine acts on. Researchers removed the ovaries of some female rats and gave some of them estradiol. They then injected epibatidine, a very strong drug that activates these receptors, into the spinal fluid and measured pain responses with a tail-flick test. Female rats reacted to pain faster than males. Removing the ovaries increased the drug's pain-relieving effect and raised the level of one nicotinic receptor type (alpha4) in the spinal cord, and estradiol treatment reduced both increases.

Chen Y, Cui Y, Lin JW et al. (2009). Modulatory role of estradiol in nicotinic antinociception in adult female rats. Life Sci. — PubMed PMID: 19427872 · doi:10.1016/j.lfs.2009.04.021

Nicotinic regulation of calcium/calmodulin-dependent protein kinase II activation in the spinal cord

Animal study, 2007. This study in mice looked at how nicotine injected into the spinal cord reduces pain responses, measured by how quickly the mice flicked their tails away from heat. Nicotine's pain-blocking effect stayed in mice lacking the alpha7 nicotinic receptor subunit but disappeared in mice lacking the beta2 subunit, and the same pattern held for nicotine's activation of a calcium-dependent signaling enzyme (CaMKII) in the spinal cord. Drugs that block L-type calcium channels stopped this enzyme activation, while a drug blocking glutamate NMDA receptors did not. The authors conclude that nicotine acting on beta2-containing nicotinic receptors in the spinal cord raises calcium inside cells, which activates CaMKII and produces pain relief; these results are only in mice.

Damaj MI (2007). Nicotinic regulation of calcium/calmodulin-dependent protein kinase II activation in the spinal cord. J Pharmacol Exp Ther. — PubMed PMID: 17041007 · doi:10.1124/jpet.106.111336

Nicotinic modulation of GABAergic synaptic transmission in the spinal cord dorsal horn

Animal study, 2005. Researchers recorded electrical signals from nerve cells in slices of spinal cord taken from newborn rats, in the part of the cord that handles pain signals. Nicotine boosted the cells' calming (GABA) signals in 86% of the nerve cells tested, raising how often these signals fired to about 500% of normal. Epibatidine, a stronger compound that acts on the same nicotine receptors, raised it to about 3000%, and drugs that block nicotine receptors stopped the effect. Nicotine also reduced a long-lasting weakening of these calming signals, which the authors say may help explain how compounds that act on nicotine receptors relieve pain. These results come only from rat tissue, not from living animals or people.

Genzen JR, McGehee DS (2005). Nicotinic modulation of GABAergic synaptic transmission in the spinal cord dorsal horn. Brain Res. — PubMed PMID: 15649448 · doi:10.1016/j.brainres.2004.10.042

Nicotine differentially activates inhibitory and excitatory neurons in the dorsal spinal cord

Animal study, 2004. Researchers studied nerve cells in the spinal cords of newborn mice to see how nicotine-like substances act on the spinal circuits that handle pain signals. Both calming (inhibitory) and signal-boosting (excitatory) nerve cells responded to nicotinic stimulation, but they used different types of nicotinic receptors, and one receptor component (alpha2) turned up in 19% of the nerve cells. The authors say this points to distinct places where nicotine-like drugs act in the spinal cord and could help explain how they relieve pain. They also note that nicotine-like substances cause mild to toxic side effects at pain-relieving doses in mice, and these results come from mouse tissue only.

Cordero-Erausquin M, Pons S, Faure P et al. (2004). Nicotine differentially activates inhibitory and excitatory neurons in the dorsal spinal cord. Pain. — PubMed PMID: 15157692 · doi:10.1016/j.pain.2004.01.034

Nicotine facilitates glycine release in the rat spinal dorsal horn

Animal study, 2001. Researchers studied slices and isolated nerve cells from the spinal cord of rats to see how nicotine affects glycine, a chemical messenger that calms pain-signalling nerve cells. Nicotine increased how often glycine was released onto these nerve cells. It did this by acting on one specific type of nicotinic receptor (the kind made of alpha4-beta2 subunits), not the alpha7 type. The authors suggest this effect may help explain how nicotine changes pain signalling and could be a cellular basis for nicotine's pain-relieving action, but the work was done only in rat tissue.

Kiyosawa A, Katsurabayashi S, Akaike N et al. (2001). Nicotine facilitates glycine release in the rat spinal dorsal horn. J Physiol. — PubMed PMID: 11579160 · doi:10.1111/j.1469-7793.2001.t01-1-00101.x

Inherited, selective hyporesponsiveness to the analgesic action of nicotine in mice

Animal study, 1996. This study in two strains of mice looked at how well nicotine relieved pain, measured by how quickly the mice flicked their tails away from a heat stimulus. Nicotine's pain-relieving effect differed significantly between the two strains, and one strain responded much less, even though both strains reacted to the pain stimulus itself in the same way and the less-responsive strain still got strong pain relief from morphine and a local anesthetic. In the less-responsive strain, nicotine's effects on movement, seizures and death were not reduced, so the weaker response applied only to pain relief. The authors conclude that genetic background matters when choosing mouse strains to study nicotine's pain-relieving effect, and that genetic analysis could help explain how that effect works.

Seale TW, Nael R, Basmadjian G (1996). Inherited, selective hyporesponsiveness to the analgesic action of nicotine in mice. Neuroreport. — PubMed PMID: 9051779 · doi:10.1097/00001756-199612200-00039

Nicotine-induced antinociception in mice: role of G-proteins and adenylate cyclase

Animal study, 1994. This study in mice looked at how nicotine reduces pain, using a tail-flick test, by blocking or boosting different signaling steps inside nerve cells in the spinal cord. Injecting pertussis toxin into the spinal fluid (0.25 and 0.50 micrograms) weakened nicotine's pain-relieving effect, and the size of that effect depended on dose and timing. Two substances that raise levels of the messenger molecule cyclic AMP also weakened nicotine's pain relief, depending on dose, and calcium seemed to be involved too. The authors conclude that nicotine's pain relief in mice may work through G-proteins and a cyclic AMP signaling pathway. These results come only from mice.

Damaj MI, Welch SP, Martin BR (1994). Nicotine-induced antinociception in mice: role of G-proteins and adenylate cyclase. Pharmacol Biochem Behav. — PubMed PMID: 8029303 · doi:10.1016/0091-3057(94)90494-4

Prenatal nicotine exposure increased duration of nicotine-induced analgesia in adult rats

Animal study, 1994. This rat study looked at whether being exposed to nicotine before birth changes how strongly nicotine relieves pain later in life. Pain relief from a single nicotine injection (1 mg/kg) was measured with a tail-flick test. At 7 months old, male rats whose mothers got nicotine throughout pregnancy had longer-lasting nicotine pain relief than control rats. When rats of both sexes were tested once a month from 2 to 7 months of age, young exposed males at first had shorter pain relief than controls. The pain relief then grew longer with age in exposed rats of both sexes, with clear differences at 6 and 7 months. The authors conclude that this greater sensitivity is not present at birth but develops later in life. These results come only from rats.

Zbuzek VK, Chin CW (1994). Prenatal nicotine exposure increased duration of nicotine-induced analgesia in adult rats. Psychopharmacology (Berl). — PubMed PMID: 7862871 · doi:10.1007/BF02245235

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

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PubMed Topic Searches

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

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Connections

• 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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