Ewan St. John Smith
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psalmotoxin.bsky.social
Ewan St. John Smith
@psalmotoxin.bsky.social
1.9K followers 1K following 1.1K posts
👨🏻‍🔬& 👨🏻‍🏫🏳️‍🌈Neuroscientist in Cambridge UK interested in the neurobiology of pain and everything to do with naked mole-rats. 🏃🏻‍♂️, 📖 & 🤘
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psalmotoxin.bsky.social
At 13:00 our @phar.cam.ac.uk lab will be live @sfn.org!

Poster N3 sees @mayadannawi.bsky.social presenting on overexpression of Prdm12 in the adult sensory nervous system

Poster O6 sees @interlukein.bsky.social presenting on loss of Piezo2 in colonic sensory neurons with age

Please drop on by 😃
Maya with details of poster Luke with details of poster
November 19, 2025 at 3:56 PM
psalmotoxin.bsky.social
Last San Diego ☀️ 🏃🏻‍♂️ = ✅
Me halfway round run with San Diego Bay and bridge in the background
November 19, 2025 at 3:13 PM
psalmotoxin.bsky.social
San Diego sparkling in the sun & 🏃🏻‍♂️ = ✅
Me halfway round with San Diego Bay in the background
November 17, 2025 at 3:16 PM
psalmotoxin.bsky.social
Had a great time at our @sfn.org #PainResearch symposium yesterday, talks covering a whole range of pain states & roles of non-neuronal cells, review article for more reading: www.jneurosci.org/content/45/4... Thanks to @cherylstucky.bsky.social, @mdburton.bsky.social & Anne-Marie Heegaard!
Poster advertising our session Me, Cheryl, Anne-Marie and Michael giving talks Ewan, Anne-Marie, Cheryl and Michael having a much deserved post-symposium dinner!
November 16, 2025 at 6:58 PM
psalmotoxin.bsky.social
Interesting @sfn.org session kicking off: “What’s in a name? Define the boundaries of neuronal cell types”.

Introduced by @vabraira.bsky.social who provided a background on her name, engaging way to emphasise the importance of names. Talks from
Jeremy Miller & @tedpricethepainguy.bsky.social
Slide explaining background go Vic’s name Slide showing progress in techniques that has enabled new ways of naming neurons Jeremy and Ted listen on as Vic introduces the session
November 16, 2025 at 6:41 PM
psalmotoxin.bsky.social
Swapped wet & windy Cambridge for wet & windy (& warmer!) San Diego, which definitely has bigger boats than Cambridge 😅

Pre-symposium warm up 🏃🏻‍♂️ = ✅: if you’re at @sfn.org & want to know more about pain, come along this afternoon 👇
Me halfway round run with USS Midway in the background
November 15, 2025 at 3:40 PM
psalmotoxin.bsky.social
Very wet & windy this morning, & extra early start as 🚕, 🚊, 🚇, ✈️ & San Diego / @sfn.org await, but 🏃🏻‍♂️ = ✅
Me recovering post-run
November 14, 2025 at 6:38 AM
psalmotoxin.bsky.social
With the annual @sfn.org meeting coming up, I'm looking forward to Saturday's symposium with @cherylstucky.bsky.social , @mdburton.bsky.social & Anne-Marie Heegaard on non-neuronal cells in #PainResearch

Here's our accompanying review!
www.jneurosci.org/content/45/4...
Figure 1. Non-neuronal–neuron communication in the skin. (1) Non-neuronal cells and extracellular matrix in the skin. (2) When in ammatory events such as IL-6, ATP, and protease production from injury or infection are introduced, it causes an activation of cells, a disruption in extracellular matrix, and damage to sensory neurons. (3) During in ammatory cascades, injured or sensitized neurons potentiate pain and the development of a chronic pain state. Figure 2. Cell–cell interactions in joint pain. Numerous pathogenic changes occur within the OA joint and other musculoskeletal conditions that can contribute to pain, including cartilage degradation, synovitis, and bone remodeling (1). Within the joint evidence has established the role of some key non-neuronal cell types that contribute to pain (2) and some of the signaling nociceptor activation and sensitization mechanisms involved (3). There is also growing evidence for cell–cell interactions within the DRG that contribute to pain (4). See text for more details. Figure 3. Keratinocytes contribute to normal touch and chemotherapy-induced mechanical sensitivity through PIEZO1. Keratinocytes in the most super cial layer of the skin respond to mechanical forces via their expression of PIEZO1 channels and activated keratinocytes release ATP which signals to P2X4 channels on cutaneous sensory nerve endings. After a patient is treated with the chemotherapeutic paclitaxel, keratinocyte PIEZO1 is sensitized; the keratinocytes release more ATP and additional mediators, resulting in greater action potential signaling in sensory neurons that is sent to the spinal cord and brain through touch and pain pathways.
November 12, 2025 at 6:19 PM
psalmotoxin.bsky.social
Wet, windy, & lots of puddle hopping required, but 🏃🏻‍♂️ = ✅
Me recovering post-run
November 12, 2025 at 7:34 AM
psalmotoxin.bsky.social
Cool & sunny out this morning, great weather for 🏃🏻‍♂️ = ✅
Still lake reflects blue sky and trees Me halfway round with autumnal trees and river in background
November 9, 2025 at 9:03 AM
psalmotoxin.bsky.social
Slow start to this #Caturday 😺😺😺
Henry, black cat, laying on the cat tree Bertie, grey cat, dozing on the bed Matilda, white cat, lying half upside down on the floor
November 8, 2025 at 7:44 AM
psalmotoxin.bsky.social
Misty out round Cambridge this morning: Friday short 🏃🏻‍♂️ = ✅
Me recovering post-run
November 7, 2025 at 7:04 AM
psalmotoxin.bsky.social
Warm out this morning for early November + dead legs = not much fun, but 🏃🏻‍♂️ = ✅
Me recovering post-run
November 5, 2025 at 7:30 AM
psalmotoxin.bsky.social
Thus: Genetic/pharmacological modulation demonstrates GPR68’s role in acid-induced colonic nociception, supporting its therapeutic potential for pain management in colitis.
Thus: Genetic/pharmacological modulation demonstrates GPR68’s role in acid-induced colonic nociception, supporting its therapeutic potential for pain management in colitis.
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
Lastly, we found that ogerin potentiated mechanical distension responses of the lumbar splanchnic nerve under acid, but not neutral conditions
(A) Schematic of experimental paradigm assessing the effects of the GPR68 PAM, Ogerin, (applied intraluminally) on colonic afferent responses to ramp distension. (B) Representative rate histograms and corresponding pressure traces from recordings showing afferent responses to ramp distensions 3-5 in pH 7.4, 6.8 and pH 6.8 + Ogerin (100 µM) groups. The dotted line highlights the sensitisation of afferent responses to distension in the pH 6.8 + Ogerin group. (C) Afferent response profiles of ramp distension 5 (0-80 mmHg) in pH 7.4 and pH 6.8 groups with and without Ogerin, normalised (norm.) to ramp distension 3 (*P < 0.05; two-way repeated measures ANOVA (main effect: P = 0.0493; F(3, 21) = 3.087) with Dunnett’s multiple comparisons test). Shaded area is SEM.
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
Conversely, the positive allosteric modulate ogerin, but not ogerin negative control, ⇧ acid-induce lumbar splanchnic nerve firing in wildtype 🐭, but not in KO 🐭
The GPR68 PAM Ogerin potentiates colonic afferent responses to acid. (A) Schematic of the experimental paradigm assessing colonic afferent responses to bath application of pH 6.0 following treatment with the GPR68 positive allosteric modulator (PAM), Ogerin, or its inactive analogue ONC (Ogerin negative control). (B) Representative rate histograms of repeated afferent stimulation with pH 6.0. The 2nd response consisted of pretreatment with either Ogerin (top) or ONC (bottom). (C) Peak change in afferent activity of response 2 (post-drug application) normalised to response 1 (pre-drug application) for vehicle, ONC or Ogerin (in GPR68+/+ and GPR68-/- mice) treated groups (Ogerin vs ONC, P = 0.0005; Ogerin vs Vehicle, P = 0.0019; Ogerin vs GPR68-/-, P = 0.0002; one-way ANOVA (main effect: P = 0.0002; F(3, 18) = 11.36); with Dunnett’s multiple comparisons test; N = 5-6 animals per group). (D) AUC of response 2 (post-drug application) normalised to response 1 (pre-drug application) for vehicle, ONC or Ogerin (in GPR68+/+ and GPR68-/- mice) treated groups (Ogerin vs ONC, P = 0.0047; Ogerin vs Vehicle, P = 0.0014; Ogerin vs GPR68-/-, P = 0.0237; one-way ANOVA (main effect: P = 0.002; F(3, 18) = 7.367); with Dunnett’s multiple comparisons test; N = 5-6 animals per group).
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
Importantly, we found that inhibiting GPR68 with ogremorphin also massively reduced acid-induced lumbar splanchnic nerve firing in wildtype 🐭
(A) Schematic of the experimental paradigm assessing colonic afferent responses to bath application of pH 5.5 in the presence and absence of the GPR68 antagonist, OGM. (B) Representative rate histograms of repeated stimulation with pH 5.5. The 2nd response consisted of pretreatment with vehicle control (DMSO) (bottom) or OGM (top). (C) Peak change in afferent activity and (D) AUC of response 2 (in the presence of OGM or vehicle) expressed as a percentage of the peak response 1 (pH 5.5 alone) (Peak change in afferent nactivity: vehicle vs 3 µM OGM, P = 0.0183; vehicle vs 30 µM OGM, P = 0.0044; one-way ANOVA (main effect: P = 0.0054; F(2, 15) = 7.537) with Dunnett’s multiple comparison test) (AUC: vehicle vs 3 µM OGM, P = 0.0081; vehicle vs 30 µM OGM, P = 0.0057; one-way ANOVA (main effect: P = 0.0045; F(2, 15) = 7.928) with Dunnett’s multiple comparison test). (E) Averaged response profiles to pH 5.5 before (response 1) and during (response 2) treatment with vehicle (grey) or 3 µM OGM (red). (N = 6 animals per group).
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
These KO 🐭 are not generally weird, lumbar splanchnic nerves respond normally to distension, bradykinin & capsaicin: a specific loss of acid-evoked firing occurs without GPR68
(A) Representative rate histogram of (i) GPR68+/+ and (ii) GPR68-/- colonic afferent responses to ramp distension (Ramp), bradykinin (BK; 1 µM) and capsaicin (Caps; 1 µM). (Bi) Response profile (P = 0.8246, two-way ANOVA; F(1, 13) = 0.05113; N = 7-8) and (Bii) peak change in afferent activity at 80 mmHg in response to ramp distension (P = 0.7861 (t, df = 0.2770, 13), unpaired t test; N = 7-8). (Ci) Response profile (P = 0.0947, two-way ANOVA; F(1, 15) = 3.182; N = 8-10) and (Cii) peak change in afferent activity in response to bradykinin stimulation (P = 0.1785 (t, df = 1.407, 16), unpaired t test; N = 8-10). (Di) Response profile (P = 0.7187, two-way ANOVA; F(1, 19) = 0.1337; N = 10-11) and (Dii) peak change in nerve activity in response to capsaicin (1 µM) stimulation (P = 0.5116, Mann-Whitney test (U = 45); N = 10-11).
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
To the colon! Acidic buffer virtually FAILED to activate lumbar splanchnic nerves from KO 🐭. a couple of years on from when @LukePaine4 first showed me the data I am still 🤯
(A) Representative rate histograms and (B) mean response profiles of GPR68+/+ (grey) and GPR68-/- (orange) colonic afferent activity in response to bath application of pH 6.5-4.0; shaded area is SEM (GPR68+/+ vs GPR68-/- main effect: P = <0.0001; two-way ANOVA; F(1,87) = 26.47). (C) Peak afferent activity at each pH (GPR68+/+ vs GPR68-/- unpaired t-test (or non-parametric equivalent); pH 6.5, P = 0.9126, t, df = 0.1115, 16; pH 6.0, P = 0.0074 (U = 18); pH 5.5, P = 0.003 (U = 10); pH 5.0, P = 0.0106 (U = 12); pH 4.0, P = 0.0008 (U = 10); N = 9-11 animals). (D) Area under the curve (AUC) for afferent responses across the pH range (GPR68+/+ vs GPR68-/- unpaired t-test (or non-parametric equivalent); pH 6.5, P = 0.2430, t, df = 1.212, 16; pH 6.0, P = 0.1145 (U = 32); pH 5.5, P = 0.003 (U = 10); pH 5.0, P = 0.0106 (U = 12); pH 4.0, P = 0.0015 (U = 12); N = 9-11 animals). U refers to the Mann-Whitney U statistic.
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
…no extracellular Ca2+ = acid activates ⇩ neurons from KO 🐭. ⇩ recapitulated by GPR68 antagonist ogremorphin / GPCR signalling inhibition in neurons isolated from wildtype 🐭
(C) Heatmaps showing Fluo-4 fluorescence during application of Ca2+ -free ECS adjusted to pH 6.5 in GPR68+/+ and GPR68-/- DRG neurons and following pre-treatment with GPR68 antagonist OGM. (D) Averaged response profiles and peak responses (E) to acidic pH across treatment conditions (pH 6.5 Control vs OGM: P = 0.0499; Control vs GPR68-/-: P = 0.0340; one-way ANOVA (main effect: P = 0.0403; F(2, 17) = 3.903) with Dunnett’s multiple comparisons test. pH 6.0 Control vs OGM: P = 0.1101; Control vs GPR68-/-: P = 0.0334; one-way ANOVA (main effect: P = 0.0451; F(2, 18) = 3.7) with Dunnett’s multiple comparisons test; n = 5-8 dishes from N = 5-6 animals) (F) Proportion of GPR68+/+ and GPR68-/- DRG neurons responding to pH 6.5 and pH 6.0 and following pre-treatment with OGM (pH 6.5 Control vs OGM: P = 0.0051; Control vs GPR68-/-: P = 0.0274; one-way ANOVA (main effect: P = 0.0085; F(2, 17) = 6.392) with Dunnett’s multiple comparisons test. pH 6.0 Control vs OGM: P = 0.0189; Control vs GPR68-/-: P = 0.0038; one-way ANOVA (main effect: P = 0.0048; F(2, 18) = 7.281) with Dunnett’s multiple comparisons test; n = 5-8 dishes from N = 5-6 animals). (G) Schematic and (H) proportion of DRG neurons responding to pH 6.0 in the presence of vehicle, YM-254890 (YM; 100 nM) or edelfosine (Edel; 10 µM) (Vehicle vs YM: P= 0.0001; Vehicle vs Edel: P = 0.0003; one-way ANOVA (main effect: P = <0.0001; F(2, 13) =21.05) with Dunnett’s multiple comparisons test; n = 5-6 dishes from N = 4-5 animals).
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
Acid evokes Ca2+ fluxes in 🐭 sensory neurons, often co-sensitive to the TRPV1 agonist capsaicin, neurons from KO 🐭 respond similarly, however…
(A) False-coloured images showing Fluo-4 fluorescence during the application of normal pH 6.0 ECS to DRG neurons isolated from GPR68+/+ and GPR68-/- mice. White arrows highlight cells responding to pH 6.0. Scale bar: 50 µM. (B) Averaged traces of pH 6.0 response and (C) peak responses across the pH range in DRG neurons isolated from GPR68+/+ and GPR68-/- mice (GPR68+/+ vs GPR68-/- P =0.9984, 0.9117, 0.8385, 0.8443 (left to right); one-way ANOVA (main effect: P = 0.0031, F(7,35) = 3.901) with Sidak’s multiple comparisons test; n = 5-7 dishes from N = 5 animals). (D) The proportion of GPR68+/+ and GPR68-/- DRG neurons responding to pH 6.5-5.0. (GPR68+/+ vs GPR68-/- P = 0.9808, 0.9984, 0.6238, 0.5866 (left to right); one-way ANOVA (main effect: P = 0.0008, F(7, 35) = 4.701) with Sidak’s multiple comparisons test; n = 5-7 dishes from N = 5 animals). The proportion of pH 6.0-responding DRG neurons also co-sensitive to capsaicin (GPR68+/+ vs GPR68-/- P = >0.9999, 0.9823, 0.9923, 0.9983 (left to right); one-way ANOVA (main effect: P = 0.3866, F(7, 33) = 1.099) with Sidak’s multiple comparisons test; N = 5-6).
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
Examining our published data (gut.bmj.com/content/68/4...) shows GPR68 is the most highly expressed PS-GPCR in 🐭 colonic sensory neurons, being enriched in TRPV1, putative nociceptive neurons
Heatmap (Fi) and Chart (Fii) showing the fraction of Gpr68-expressing sensory neurons which coexpress Trpv1. Heatmap showing the expression (logTPM) of Gpr4, Gpr65, Gpr68 and Gpr132 as well as ASIC1-5 and Trpv1 in murine colonic sensory neurons
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
GPR68 is ⇧ in🧍ulcerative colitis & Crohn’s disease bowel vs. controls (no ⇧ seen in🧍recurrent abdominal pain); & like others we see that 🐭 without GPR68 (KO 🐭) = ⇩ colitis
(A) Expression (RPKM, Reads Per Kilobase Million) of GPR68 in colonic biopsies taken from people with no inflammation (NI), ulcerative colitis (UC), drug-naïve and drug-treated Crohn’s disease (CDN and CDT, respectively) and recurrent abdominal pain (RAP). Median, interquartile range (box), and full range (whiskers) is shown. (GPR68 CDN vs NI, P = 2.6 x 10-4; CDT vs NI, P = 5.8 x 10-3; UC vs NI, P = 2.8 x 10-4; one-way ANOVA (main effect: P = 6.53 x 10-5; F(4, 58) = 3.579) with Benjamini-Hochberg post-hoc test). Disease activity index (DAI) over the course of 1.5%-induced colitis in GPR68+/+ and GPR68-/- mice (GPR68+/+ vs GPR68-/- Day 6, P = 0.003**; Day 7, P = 0.0003***; two-way ANOVA (main effect: P = <0.0001; F(2, 112) = 40.57) with Tukey’s post-hoc test). The H2O control group consisted of GPR68+/+ mice only.
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
Acid-induced pain is complex: there are LOTS of acid sensors; acid-induced pain is common in the animal kingdom, but not naked mole-rats, see @interlukein.bsky.social’s review royalsocietypublishing.org/doi/10.1098/...
Membrane topologies of proton-sensitive receptor subunits. Schematic diagram of the basic structure of proton-sensitive receptors, with residues or regions important for proton sensitivity annotated (yellow—highly conserved among family members; white—less conserved or important in some, but not all, family members). Functional ASICs, K2Ps and TRPs are multimeric, but for simplicity only one subunit of each receptor is shown. Phylogeny of general nociception and acid nociception. Annotated phylogenetic tree indicating the presence of general nociceptors, observation of acid nociception and functional expression of proton-sensitive receptors. Annotation is limited by the rarity of molecular studies focusing on lower-order species. Expression of proton-sensitive receptors is only acknowledged for those species where proton sensitivity of at least one member of the group in question has been empirically proven. Naked mole-rat sitting on a glove
November 4, 2025 at 4:49 PM
psalmotoxin.bsky.social
For the acid aficionados, it was shown in the 1920s that neutralisation of acid could ameliorate the pain induced by acidic ulcers (translation as alt text) link.springer.com/article/10.1...
An otherwise healthy hiker came to the outpatient clinic with a furuncular abscess on one side of his buttock. The abscess, located deep in the fat pad, was infiltrated by tissue extending across the entire buttock. Due to severe pain and difficulty sitting, the patient requested an incision, whose pain-relieving effect he knew from previous boils. The abscess was punctured, but only a few drops of thick pus were drained, followed by the injection of 15 cc of phosphate buffer solution (pH 9.1) (bacteriologically confirmed: staphylococcus). Just a few minutes later, the patient expressed great surprise that he could walk freely and, above all, sit fully on his buttocks without significant discomfort. The pain relief was then permanent. After an initial increase in the hardness of the infiltrate, the abscess healed without fistula formation within a few days.
November 4, 2025 at 4:49 PM