Differential coding of cold allodynia – a fmri study

Aim of Investigation: The pathophysiology of cold allodynia, a typical sign of neuropathic pain, is unclear. Two complementary mechanisms have been postulated: sensitization of peripheral nociceptive structures and disinhibition of central processing of C-fiber nociceptive input. Aim of this study was to explore the „peripheral sensitization“ and „central disinhibition“ mechanism of cold allodynia in humans.

Methods: In eight healthy male volunteers, topical menthol (peripheral sensitization of C-fibers) or conduction block of A-fiber input (central disinhibition due to mechanical conduction block of myelinated A-fibers) was applied to evoke cold allodynia in the innervation territory of the right superficial radial nerve. fMRI (1.5 T) was performed during menthol-induced and block-induced cold allodynia. Using a block-design, a thermode applied randomised tonic cold stimuli at four different levels below / above the individual cold pain threshold. Bold signal changes were contrasted for both types of cold allodynia using SPM2.

Results: Both interventions induced stable cold allodynia (decrease of cold pain threshold of 13.4±3.8°C / 10.6±4.4°C (p<0.001)). A direct comparison of both types of cold allodynia showed stronger BOLD signal increases in left medial thalamus (p=0,008), anterior cingulate cortex (p=0,01)and medial prefrontal cortex during block-induced allodynia. By contrast, menthol-induced cold allodynia activated stronger the lateral left thalamus (p=0,027) relative to block-induced allodynia (all p: FDR corrected). Mean pain intensity was comparable for both types of cold allodynia (p>0.1).

Conclusion: Cold allodynia is processed in different cerebral areas depending on the underlying mechanism of generation. Peripheral sensitization favoured a preferential activation of the thermoreceptive spinothalamic pathway in the menthol model, whereas A-fiber block selectively attenuated the thermoreceptive input through the lateral pathway and produced a consistent increase in cold-induced activity within the medial system. This shows that activity in the thermoreceptive system normally inhibits cold-evoked activity in the medial nociceptive pathway – A-fiber block disinhibits activity in the ascending polymodal nociceptive channel.

Acknowledgments: DFG (Ba 1921), BMBF, DFNS (01EM05/04), BMBF (01 GO 0511), Alexander von Humboldt-Foundation, unrestricted educational grant Pfizer, Germany.