Differential coding of cold allodynia – A fmri study—A

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