Role of the endocannabinoid system in human pain sensitivity, pain plasticity, pain habituation, and neurogenic and non-neurogenic inflammation
Final Report Abstract
This project focused on cannabinoid control of somatosensory perception, in particular pain and pain plasticity in humans. The project employed state-of-the-art psychophysical methods, human surrogate models of pain plasticity, cannabinoid pharmacological modulation, and cannabinoid pain genetics. To this end we refined a previously developed model of synaptic plasticity of pain pathways induced by HFS, i.e. brief electrical high frequency stimulation (long-term potentiation of pain, in short “pain LTP”), a perceptual correlate in healthy human subjects of electrophysiological recording of plasticity of nociceptive signal processing in the spinal cord in animals. The major findings were as follows: First, we demonstrated that human pain-LTP is a robust and reliable pain plasticity model with hyperalgesia typically lasting for about two days (i.e. decremental early LTP1), however, about 20% of subjects exhibited signs of transition to persistent late LTP2, a possible signature of being prone to a more chronic hyperalgesia time course. Second, using selective temporary nerve blocks we could show that the main driver of pain-LTP is capsaicin-sensitive C-fiber input. Third, we demonstrated that low frequency stimulation (LFS) partially reversed HFS-induced pain-LTP, i.e. induced long-term depresssion of pain (pain-LTD), and that repeated LFS erased pain-LTP completely. We also corroborated the complete U-shape of pain-LTD and delineated optimal stimulation parameters for pain-LTD, which in our hands represents the mechanism of low frequency transcutaneous electrical nerve stimulation (acupuncture-like TENS). In a core part of the project we tried to establish phenotype-genotype associations of pain phenotypes and cannabinoid genotypes. While we found an apparent association in a small cohort (n=53) by the end of the first funding period, which relied on very small numbers of cannabinoid variants (homozygous variant carriers typically < 10% of the cohort), this turned out to be an instable finding that could not be substantiated in a larger cohort (n=153) of second interim analysis. All candidate polymorphisms were either not significant in ANOVA or significant ANOVAs were related to heterozygous effect. Thus, this high risk part of the project was not successful. We decided to use the funds for further building of the phenotype database for later association studies (e.g. on polymorphisms of the TRPV1 receptor, for which we found that homozygous carriers of the loss-of-function variant Ile585val were completely devoid of neuropathic hyperalgesia). One high risk part of the project (CB1 receptor PET) could not be carried out, since the CB1 ligand did not become available for human use. Instead we performed an alternative PET project targeting spinal cord glucose metabolism (by 18FDG-PET) as a marker of ongoing noxious input to the spinal dorsal horn in collaboration with the Institute of Clinical Radiology and Nuclear Medicine (Prof. Schönberg). Pharmacological modulation by cannabinoid drugs, namely sustained treatment with high dose PEA oral or locally did not precipitate any significant modulation of nociceptive or non-nociceptive perception, neither in normal or UVB-inflamed skin, nor of pain-LTP. Likewise, sustained treatment with an FAAH inhibitor (ASP8477) was ineffective. In contrast, the general anaesthetic propofol (suspected to modulate cannabinoid tone) led to erasure of pain-LTP. It has to be elucidated whether this is propofol-specific or related to general anaesthesia. Neuropathic patients with autoimmune spinal inflammation (neuromyelitis) exhibited strong modulation of mechanical hyperalgesia by endogenous 2-AG. In conclusion, an impact of the cannabinoid system on normal pain perception or acute pain plasticity, nor cannabinoid pharmacological or genetic modulation could be shown. However, our data support a contribution to hyperalgesia reversal and to homeostatic control under neuropathic pain conditions.
Publications
- (2008) A familybased investigation of cold pain tolerance. Pain 138:111-118
Birklein F, Depmeier C, Rolke R, Hansen C, Rautenstrauss B, Prawitt D, Magerl W
(See online at https://doi.org/10.1016/j.pain.2007.11.012) - (2010) Basal opioid receptor binding is associated with differences in sensory perception in healthy human subjects: a [18F]diprenorphine PET study. NeuroImage 49:731-737
Mueller C, Klega A, Buchholz HG, Rolke R, Magerl W, Schirrmacher R, Schirrmacher E, Birklein F, Treede RD, Schreckenberger M
(See online at https://doi.org/10.1016/j.neuroimage.2009.08.033) - (2011) Analysis of hyperalgesia time courses in humans following painful electrical high-frequency stimulation identifies a possible transition from early to late LTP-like pain plasticity. Pain 152: 1532-1539
Pfau DB, Klein T, Putzer, D, Pogatzki-Zahn E, Treede RD, Magerl W
(See online at https://doi.org/10.1016/j.pain.2011.02.037) - (2012) Experimental characterization of the effects of acute stresslike doses of hydrocortisone in human neurogenic hyperalgesia models. Pain 153: 420-428
Michaux GP, Magerl W, Anton F, Treede RD
(See online at https://doi.org/10.1016/j.pain.2011.10.043) - (2013) The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with Neuromyelitis Optica. PLoS One 8:e71500
Pellkofer HL, Havla J, Hauer D, Schelling G, Azad SC, Kuempfel T, Magerl W, Huge V
(See online at https://doi.org/10.1371/journal.pone.0071500) - (2013) The pattern and time course of somatosensory changes in the human UVB sunburn model reveal the presence of peripheral and central sensitization. Pain 154:586-597
Gustorff B, Sycha T, Lieba-Samal D, Rolke R, Treede RD, Magerl W
(See online at https://doi.org/10.1016/j.pain.2012.12.020) - (2014) An improved model of heat-induced hyperalgesia - repetitive phasic heat pain causing primary hyperalgesia to heat and secondary hyperalgesia to pinprick and light touch. PLoS One 9: e99507
Jürgens T, Sawatzky A, Henrich F, Magerl W, May A
(See online at https://doi.org/10.1371/journal.pone.0099507) - (2015) Capsaicin-sensitive C and A-fiber nociceptors control LTP-like pain amplification in humans. Brain 138:2505-2520
Henrich F, Magerl W, Klein T, Greffrath W, Treede RD
(See online at https://doi.org/10.1093/brain/awv108) - (2016) Electrical high-frequency stimulation of the human thoracolumbar fascia evokes long-term potentiation-like pain amplification. Pain 157:2309-2317
Schilder A, Magerl W, Hoheisel U, Klein T, Treede RD
(See online at https://doi.org/10.1097/j.pain.0000000000000649) - (2016) High-frequency modulation of rat spinal field potentials: effects of slowly conducting muscle vs. skin afferents. J Neurophysiol. 115:692-700
Zhang J, Hoheisel U, Klein T, Magerl W, Mense S, Treede RD
(See online at https://doi.org/10.1152/jn.00415.2015)
