On the function endogenous pain controlling systems in healthy subjects and patients with peripheral or central neuropathic pain

Introduction and aim: Activity in the nociceptive system is modulated by descending inhibitory and facilitatory supraspinal endogenous control. Altered balance between inhibition and facilitation has been suggested to at least partly explain the maintenance of some persistent pain conditions. The aim was to investigate the influence of supraspinal descending endogenous modulation induced by heterotopic noxious conditioning stimulation (HNCS) on spontaneous ongoing pain and dynamic mechanical allodynia in painful peripheral neuropathy (study II) and in central post stroke pain (CPSP) (study III). In addition, the influence of ongoing pain and HNCS on pain sensitivity in a pain-free area was assessed and compared to age- and sex-matched healthy controls (study II and III). To prepare for a proper study design in these studies potential side and time dependant alterations in pain sensitivity were examined in healthy volunteers (study I). The possible involvement of spinal dorsal horn 5HT3-receptors in spontaneous ongoing pain and dynamic mechanical allodynia in patients with peripheral neuropathy, an hypothesis derived from animal model research, was examined following intravenous infusion of the 5HT3-antagonist ondansetron (study IV).

Methods: Ischemia-induced HNCS was used to activate endogenous pain controlling systems. In patients, the intensity of spontaneous ongoing- and brush-evoked pain was assessed. A semi-quantitative brushing technique was employed, combined with a computerized visual analogue scale (VAS) to monitor the allodynic percept over time and calculating the area under the VAS curve as the total brush-evoked pain intensity. Before, during and following HNCS in study I and II heat- and pressure pain thresholds and sensitivity to suprathreshold heat- and pressure pain were assessed in the pain-free area in patients. For comparison pain sensitivity was assessed also in controls. In healthy volunteers identical assessments were performed bilaterally on the thighs (study I). Before and during 3 hours following an intravenous infusion of ondansetron in study IV the intensity of spontaneous ongoing- and brush-evoked pain was assessed using the described methods.

Results: During unilateral HNCS of the left arm in healthy volunteers no side differences in bilaterally decreased pain sensitivity were found. However, a time factor was demonstrated for reduced suprathreshold pain sensitivity as it was found only on the lastly assessed side without side differences in magnitude. During HNCS in patients with painful peripheral neuropathy the intensity of spontaneous ongoing pain was significantly decreased, whereas brush-evoked pain was unaltered. No significant changes of neither spontaneous- nor brush-evoked pain were found in patients with CPSP. At baseline, significantly increased pressure pain sensitivity in a pain-free area was demonstrated in CPSP patients compared to controls but not in patients with painful peripheral neuropathy. During HNCS higher pressure pain thresholds were demonstrated in patients with painful peripheral neuropathy and CPSP as well as in healthy controls. Intravenous infusion of the 5HT3-antagonist ondansetron failed to alter the intensity of spontaneous ongoing- and brush-evoked pain in patients with peripheral neuropathy.

Conclusions: During HNCS the patients with painful peripheral neuropathy reported reduced intensity of the spontaneous pain whereas the intensity of brush-evoked pain was unaltered. No significant alteration of the intensity of spontaneous- or brush-evoked pain were found in CPSP patients indicating lack of modulation from endogenous pain controlling systems on nociceptive activity primarily generated in the stroke affected brain. In CPSP patients the increased pressure pain sensitivity in a remote pain-free area at baseline suggests alterations in corticofugal control of nociceptive sensitivity due to the brain lesion. During HNCS patients with painful peripheral neuropathy and CPSP activated pain modulatory systems interacting with nociceptive input from the spinal level equal to controls. Intravenous infusion of ondansetron did not influence the intensity of brush-evoked- or spontaneous ongoing pain in patients with peripheral neuropathy, indicating lack of involvement of 5HT3 receptors in the maintenance of dynamic mechanical allodynia.

List of scientific papers

I. Tuveson B, Leffler AS, Hansson P (2006). "Time dependent differences in pain sensitivity during unilateral ischemic pain provocation in healthy volunteers." Eur J Pain 10(3): 225-32
https://pubmed.ncbi.nlm.nih.gov/15919219

II. Tuveson B, Leffler AS, Hansson P (2007). "Heterotopic noxious conditioning stimulation (HNCS) reduced the intensity of spontaneous pain, but not of allodynia in painful peripheral neuropathy." Eur J Pain 11(4): 452-62. Epub 2006 Aug 4
https://pubmed.ncbi.nlm.nih.gov/16889998

III. Tuveson B, Leffler AS, Hansson P (2008). "Influence of heterotopic noxious conditioning stimulation on spontaneous pain and dynamic mechanical allodynia in central post-stroke pain patients." (Submitted)

IV. Tuveson B, Leffler AS, Hansson P (2008). "Ondansetron, a 5HT3-antagonist, does not alter dynamic mechanical allodynia or spontaneous ongoing pain in peripheral neuropathy." (Submitted)