Pain sensitivity and modulation

Pain and nociception are not interchangeable

Nociception is neural encoding of noxious stimuli, whereas the IASP definition describes pain as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. Sensory input, context, learning, expectation, and physiological state can influence that experience. A detection threshold, a tolerance endpoint, a numerical intensity rating, regional activation, connectivity, and clinical pain prevalence are different measurements. This exhibit does not collapse them into one female or male pain system.

The priority studies categorize participants as men and women or male and female. Many underlying pain studies use the words sex and gender interchangeably instead of documenting the biological variable consistently. That weakens measurement quality but does not justify discarding the observed group averages. Sexual orientation was not reported in the priority studies and is neither a proxy for sex nor an available causal explanation.

Average experimental pain differences

Graziano and colleagues synthesized 90 cross-sectional studies. As of 20 July 2026, the publisher lists the article as In Press, Corrected Proof, available online 3 April 2026, rather than as a paginated final issue. Its endpoint totals are 7,464 for threshold, 4,935 for tolerance, and 4,911 for intensity; these are not guaranteed to be unique participants, and the public record does not provide exact pooled female and male counts.

Men had higher average thresholds, d = 0.66, higher average tolerance, d = 0.79, and lower reported intensity, d = -0.58 under the authors’ coding. The study detected publication bias for all three outcomes and substantial heterogeneity. Stimulus and sample type moderated some results. It was not preregistered, although its protocol followed an approved dissertation plan. These limitations lower confidence in the exact pooled magnitudes without erasing the average differences.

The atlas intentionally shows no highlighted brain region when this evidence group is selected. A psychophysical outcome is produced by a whole experimental system and does not identify the anatomical source of the sex difference.

Shared acute-pain maps and a null sex contrast

Xu and colleagues preregistered a coordinate-based activation-likelihood meta-analysis covering 222 experiments from 200 papers and 3,816 participants. The dedicated sex analysis was a between-experiment contrast of 22 all-female experiments, N = 338, and 30 all-male experiments, N = 533, not a participant-level comparison within the same experiments.

Neither direction of sex contrast produced a suprathreshold cluster after 10,000 label permutations at p < 0.001 with inclusive main-effect masking and k > 25. The formal conjunction identified left supramarginal gyrus/PFop in the inferior parietal lobule plus bilateral insula. The parietal-operculum mesh is only the nearest available gross proxy and must not be read as an SII finding. The highlighted meshes do not prove that the sexes have equivalent neural pain responses, exclude differences below the method’s resolution, or authorize a psychological interpretation from regional activation.

PAG connectivity is limited evidence

Linnman and colleagues performed a secondary analysis pooling identical pretreatment scans from three earlier placebo, nocebo, and acupuncture experiments. The pooled sample comprised 60 healthy adults, 26 men and 34 women, acquired across two scanner models and tested with individually calibrated low and high heat. Pain thresholds, ratings, and PAG activation magnitude did not differ by sex. Both sexes showed increased high-pain PAG coupling with distributed sensorimotor, cerebellar, and thalamic territories.

The study also found stronger left-PAG coupling in men with left amygdala, left thalamus, right putamen, and right caudate, all surviving whole-brain family-wise correction. Women showed stronger coupling with right supplementary motor area, while the right PAG seed showed no sex effects. The exhibit does not selectively convert target nodes into greater regional activation. It displays the seed and named targets because the atlas cannot draw the studied edges.

This was one small pooled study without independent replication. Menstrual phase and oral contraception were not controlled, and the study did not report sexual orientation. The result is a plausible connectivity hypothesis, not a stable female-male circuit map.

Peripheral nociceptor mechanisms

Stratton and colleagues published a final edited Brain article combining mouse, macaque, and cultured human dorsal-root-ganglion neurons. Human tissue came from 6 male and 4 female donors across the complete work, but the prolactin electrophysiology comparison used 4 male and 3 female donors and the orexin-B comparison used 3 male and 2 female donors. The reported cell-level F tests did not model donor clustering, so the 114 male and 106 female cells reported across the human work are not independent people or biological replicates.

Prolactin selectively increased excitability in female donor neurons, while orexin B selectively increased excitability in male donor neurons. The cross-species pattern is mechanistically striking, but the orexin-B human experiment included only 3 male and 2 female donors and the receptor-expression interpretation remained preliminary. Dorsal-root-ganglion neurons are peripheral and absent from this brain atlas. These experiments do not show that either pathway explains population pain differences or that a sex-specific clinical treatment is effective.

Endogenous modulation and menstrual-cycle uncertainty

Conditioned pain modulation asks whether one noxious stimulus reduces the response to another. Reviews of 17 DNIC studies and 46 CPM articles found results that varied with test stimulus, conditioning stimulus, endpoint, and sample. Some pain-report outcomes favored stronger inhibition in males, while threshold and reflex outcomes sometimes reversed. A direct 54-person study found no sex or contraceptive-group effect. A systemic modulation protocol is not, by itself, a PAG measurement.

Menstrual-cycle findings are similarly unsettled. An older 16-study meta-analysis suggested modest phase variation. A 2015 review found that better-controlled healthy-volunteer studies were generally null, and a 2020 update found five reports of variation and four null reports. Cycle-phase effects remain inconsistent and method-sensitive because phase definitions, ovulation confirmation, hormone measurement, and contraceptive handling vary. Systemic cycle evidence does not localize an effect to the hypothalamus.

What these results do not establish

The strongest quantitative evidence here concerns average experimental behavior. The localized neural evidence is either a thresholded null contrast or one small, unreplicated connectivity study. The donor-cell work is peripheral and ex vivo. None of these findings identifies the cause of chronic pain in one person, supports a diagnostic sex classifier, or implies that all members of either sex respond alike.

The atlas highlights locations, not effect direction or magnitude. A bilateral mesh can overstate a unilateral result, a procedural PAG cannot reproduce a histological boundary, and an intentionally blank highlight state means that no brain region is claimed. The display does not encode an individual’s pain, treatment response, or physiology.

Reviewed status: Owner review was completed by Taig Mac Carthy on 21 July 2026 for publication. Reviewed status records editorial approval; it is not clinical endorsement.