Background & Aims
The thermal grill illusion (TGI) induces a perception of burning pain in response to alternating adjacent innocuous warm and cool bars stimuli applied simultaneously1-4. This illusory painful experience is often compared to the burning sensation associated with cold pain, or to cold allodynia experienced by individuals with neuropathic pain5. There are several theories regarding the underlying mechanisms of TGI, but these have yet to be confirmed. The most prominent theories point to integration at the level of the spinal dorsal horn6-9. Currently, it is unknown whether TGI directly activates peripheral nociceptors, thus inducing peripheral sensitization, and if it can sensitize second-order fibres inducing central sensitization. We aim to determine whether the thermal grill can elicit brush allodynia, primary hyperalgesia, and secondary hyperalgesia. We hypothesize that the thermal grill will not elicit brush allodynia or primary hyperalgesia but will elicit secondary hyperalgesia.
Methods
Fifty-two participants (26 males/26 females; mean age ±SD: 23.5 ±4.8 years) received a phasic heat pain paradigm with individually calibrated thermal grill stimulation (non-painful and between 5-42°C): 8 repetitions, 40s stimulation, 20s inter-stimulus interval. Participants rated pain intensity (0-100 verbal numeric rating scale, vNRS) and stimulus unpleasantness (0-100 vNRS). We measured brush allodynia as a binary choice of pain/no pain in response to a brush in the stimulation site area post-PHP. A Chi-square test was used to test statistical significance (p<0.05). Primary hyperalgesia was calculated by differences to pain intensity ratings to mechanical pinprick stimuli pre-PHP vs. post-PHP. We used a paired Wilcoxon signed rank test to test significance (p<0.05). Finally, secondary hyperalgesia was calculated as the area of heightened sensitivity to mechanical pinpricks around the PHP stimulation site, as previously done10. A one-sample t-test tested for significance (p<0.05).
Results
No participants developed brush allodynia from PHP with a thermal grill. The thermal grill led to primary hyperalgesia (p=0.0002; Hedges’ g=-0.48) and secondary hyperalgesia (p=2.42×10-18; Hedges’ g=1.83). All but one participant developed secondary hyperalgesia. There were no sex differences in primary hyperalgesia (p=0.181) or area of secondary hyperalgesia (p=0.058). When investigating participants who received thermal stimuli only within the innocuous range (19-41°C; N=7), secondary hyperalgesia developed (p=0.003; Hedges’ g=1.37), but primary hyperalgesia did not (p=0.137; Hedges’ g = 0.56). Further, primary and secondary hyperalgesia (for the whole sample of n=52) were significantly correlated together (?=0.29, p=0.037).
Conclusions
These findings show that TGI can induce both primary and secondary hyperalgesia. The effects of TGI on primary hyperalgesia appear to be primarily driven by cool temperatures that could potentially activate primary noxious thermal-sensitive afferents (<19°C)11,12, while the effect on secondary hyperalgesia appear to exist regardless of noxious or innocuous component temperature input. These findings indicate that TGI integration either integrate peripherally or within the spinal cord, or one of the innocuous component temperatures can sensitize second-order nociceptive fibres. Further, these findings show that there is at least some integration of TGI within the spinal cord, rather than it being a solely supraspinal process. Future studies must investigate peripheral sensitization using a fixed temperature thermal grill, across participants, in innocuous ranges to test whether the standard thermal grill activates peripheral nociceptors.
References
1.Thunberg, T. Förnimmelserna vid till samma ställe lokaliserad, samtidigt pågående köld-och värmeretning. Uppsala Läkfören Förh 2, 489-495 (1896).
2.Alrutz, S. On the temperature-senses. Mind 7, 141-144 (1898).
3.Harper, D.E. & Hollins, M. Conditioned pain modulation dampens the thermal grill illusion. Eur J Pain 21, 1591-1601 (2017).
4.Fardo, F., Beck, B., Allen, M. & Finnerup, N.B. Beyond labeled lines: A population coding account of the thermal grill illusion. Neurosci Biobehav Rev 108, 472-479 (2020).
5.Lindstedt, F., et al. Evidence for thalamic involvement in the thermal grill illusion: an FMRI study. PLoS One 6, e27075 (2011).
6.Craig, A.D. & Bushnell, M.C. The Thermal Grill Illusion: Unmasking the Burn of Cold Pain. Science 265, 252-255 (1994).
7.Craig, A.D., Reiman, E.M., Evans, A. & Bushnell, M.C. Functional imaging of an illusion of pain. Nature 384, 258-260 (1996).
8.Green, B.G. Synthetic heat at mild temperatures. Somatosens Mot Res 19, 130-138 (2002).
9.Fardo, F., Finnerup, N.B. & Haggard, P. Organization of the Thermal Grill Illusion by Spinal Segments. Ann Neurol 84, 463-472 (2018).
10.Salomons, T.V., Moayedi, M., Erpelding, N. & Davis, K.D. A brief cognitive-behavioural intervention for pain reduces secondary hyperalgesia. Pain 155, 1446-1452 (2014).
11.Kwan, K.Y. & Corey, D.P. Burning cold: involvement of TRPA1 in noxious cold sensation. J Gen Physiol 133, 251-256 (2009).
12.Vay, L., Gu, C. & McNaughton, P.A. The thermo-TRP ion channel family: properties and therapeutic implications. Br J Pharmacol 165, 787-801 (2012).
Presenting Author
Matthew Cormie
Poster Authors
Topics
- Mechanisms: Biological-Systems (Physiology/Anatomy)