The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica

Abstract

Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG.

Figure 1. Pattern of sensory changes in patients with NMO (normalized to mean and standard deviation of healthy control group).

A: The sensory profile by comprehensive quantitative sensory testing (QST) shows significant sensory loss (negative z-values) for thermal detection (CDT, WDT, TSL) and vibration detection (VDT) in both extremities, significant sensory gain (positive z-values) for noxious heat (HPT) in the hand dorsum. B: Patients with NMO experienced pronounced dysesthesia to non-noxious mechanical and thermal stimulation in both extremities, namely pain to stroking with non-noxious light tactile stimuli (dynamic mechanical allodynia DMA) and paradoxical heat sensation (PHS) to stimulation with non-noxious cold stimuli during the TSL procedure (alternating cold and warm stimuli). *p<0.05, **p<0.01, ***p<0.001, t-test.

Figure 2. Thermal thresholds in NMO.

A: Heat pain thresholds in patients with NMO (NMO) compared to healthy controls (HC) differed significantly in the hands, but not feet. B: Patients with NMO (NMO) in patients with an acute MRI-verified cervical lesion (NMO w) were significantly more heat pain-sensitive in both extremities and also tended to be more cold pain-sensitive than patients without (NMO w/o). For both thermal pain modalities the hyperalgesia tended to be more pronounced in the hands than feet. C: Collapsing data from both extremities revealed that patients with an acute MRI-verified cervical lesion (NMO w) were significantly more cold pain-sensitive than patients without (NMO w/o). D: Correlations of heat pain thresholds to the time span since the last relapse of an acute NMO attack was high in the hand (closed circles; r = 0.77) and feet (open circles; r = 0.68). This correlation also persisted at the same level, when normalized for gender and age. The correlations indicated that NMO relapses may have induced a severe heat hyperalgesia that subsided slowly during the course of remission. ⁽*⁾p<0.10, *p<0.05, **p<0.01, ***p<0.001, t-test.

Figure 3. Abnormal somatosensory findings in NMO.

Pattern of abnormal somatosensory findings in patients with NMO encompassing sensory gains (black bars) and sensory losses (grey bars). Highly significant loss of sensitivity was prevalent for all non-nociceptive detection (except for tactile detection MDT, which exhibited also a similar number of abnormal gains in sensitivity). Highly significant gain of sensitivity was prevalent for all pain thresholds (except for cold pain threshold CPT) and for the painful dysesthesias elicited by non-noxious stroking tactile stimuli (dynamic mechanical allodynia DMA) and heat pain sensation elicited by non-noxious cold stimuli during the TSL procedure (paradoxical heat sensation PHS). Healthy controls did not exhibit abnormal frequencies in any of the 13 QST parameters. *p<0.05, **p<0.01, ***p<0.001, Yates-corrected Chi²-test.

Figure 4. Endocannabinoid plasma levels in NMO.

Mean plasma levels of the endogenous cannabinoid lipids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamide (AEA, anandamide) were increased in patients with NMO compared to age matched healthy controls. (*)p<0.10, **p<0.01.

Figure 5. Correlations between pain sensitivity and endocannabinoid plasma levels.

The figure displays correlations of quantitative sensory testing of pain sensitivity (normalized pain thresholds) to plasma concentrations of the cannabinoid lipids N-arachidonoylethanolamide (AEA, anandamide) and 2-arachidonoylglycerol (2-AG) in patients with NMO. Therefore, the results of all QST parameters testing mechanical (PPT, MPT) or thermal (CPT, HPT) pain sensitivity in each patient and each test site (both hands and feet) were analysed. A: The plasma concentration of AEA was weakly positively correlated to normalized pain thresholds collapsing estimates in the hand and feet dorsums. B: The plasma concentration of 2-AG was significantly negatively correlated to normalized pain thresholds. C: Correlation of 2-AG concentrations to normalized pain thresholds in hand and feet dorsums differed significantly between thermal (no correlation) and mechanical pain thresholds (substantial negative correlation). The latter varied by more than four standard deviations between the lowest and highest concentration of plasma 2-AG in an NMO patient. Thermal pain thresholds (open symbols), mechanical pain thresholds (closed symbols).