Introduction: Cannabis-based medicines have a number of therapeutic indications, including anti-inflammatory and analgesic effects. The endocannabinoid receptor system, including the cannabinoid receptor 1 (CB₁) and receptor 2 (CB₂) and the endocannabinoids, are implicated in a wide range of physiological and pathophysiological processes. Pre-clinical and clinical studies have demonstrated that cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis. The aim of this study was to determine whether the key elements of the endocannabinoid signalling system, which produces immunosuppression and analgesia, are expressed in the synovia of patients with osteoarthritis (OA) or RA. Methods: Thirty-two OA and 13 RA patients undergoing total knee arthroplasty were included in this study. Clinical staging was conducted from x-rays scored according to Kellgren-Lawrence and Larsen scales, and synovitis of synovial biopsies was graded. Endocannabinoid levels were quantified in synovial fluid by liquid chromatography-mass spectrometry. The expression of CB₁ and CB₂ protein and RNA in synovial biopsies was investigated. Functional activity of these receptors was determined with mitogen-activated protein kinase assays. To assess the impact of OA and RA on this receptor system, levels of endocannabinoids in the synovial fluid of patients and non-inflamed healthy volunteers were compared. The activity of fatty acid amide hydrolase (FAAH), the predominant catabolic endocannabinoid enzyme, was measured in synovium. Results: CB₁ and CB₂ protein and RNA were present in the synovia of OA and RA patients. Cannabinoid receptor stimulation of fibroblast-like cells from OA and RA patients produced a time-dependent phosphorylation of extracellular signal-regulated kinase (ERK)-1 and ERK-2 which was significantly blocked by the CB₁ antagonist SR141716A. The endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) were identified in the synovial fluid of OA and RA patients. However, neither AEA nor 2-AG was detected in synovial fluid from normal volunteers. FAAH was active in the synovia of OA and RA patients and was sensitive to inhibition by URB597 (3'-(aminocarbonyl) [1,1'-biphenyl]-3-yl)-cyclohexylcarbamate). Conclusion: Our data predict that the cannabinoid receptor system present in the synovium may be an important therapeutic target for the treatment of pain and inflammation associated with OA and RA.

Single-unit extracellular recordings of spino-parabrachial (spino-PB) neurons ( n = 53) antidromically driven from the contralateral parabrachial (PB) area were performed in the lumbar cord in anesthetized rats. All the spino-PB neurons were located in the lamina I of the dorsal horn. Their axons exhibited conduction velocities between 2.8 and 27.8 m/s, in the thin myelinated fibers range. They had an extremely low spontaneous activity (median = 0.064 Hz) and a small excitatory receptive field (≤2 toes or pads). They were all activated by both peripheral A (mainly Aδ) and C fibers after intense transcutaneous electrical stimulation. Their discharge always increased in response to noxious natural stimuli of increasing intensities. The great majority (75%) of spino-PB neurons were nociceptive specific, i.e., they were excited only by noxious stimuli. The remaining (25%) still were excited primarily by noxious stimuli but also responded moderately to innocuous stimuli. Almost all spino-PB neurons (92%, 49/53) were activated by both mechanical and heat noxious stimuli. Among them, 35% were in addition moderately activated by noxious cold (thresholds between +20 and −10°C). Only (8%, 4/53) responded exclusively to noxious heat. Spino-PB neurons clearly encoded the intensity of mechanical ( n = 39) and thermal ( n = 38) stimuli in the noxious range, and most of the individual stimulus-response functions were monotonic and positive up to 40/60 N · cm⁻²and 50°C, respectively. For the mechanical modality, the mean threshold was 11.5 ± 1.25 N · cm⁻²(mean ± SE), the response increased almost linearly with the logarithm of the pressure between 10 and 60 N · cm⁻², the mean p₅₀(pressure evoking 50% of the maximum response) and the maximum responsiveness were: 30 ± 2.4 N · cm⁻²and 40.5 ± 5 Hz, respectively. For the thermal modality, the mean threshold was 43.6 ± 0.5°C, the mean curve had a general sigmoid aspect, the steepest portion being in the 46–48°C interval, the mean t₅₀and the maximum responsiveness were: 47.4 ± 0.3°C and 40 ± 4.4 Hz, respectively. Most of the spino-PB neurons tested (13/16) had their noxiously evoked responses clearly inhibited by heterotopic noxious stimuli. The mean response to noxious stimuli during heterotopic stimuli was 31.7 ± 6.1% of the control response. We conclude that the nociceptive properties of the lamina I spino-PB neurons are reflected largely by those of PB neurons that were suggested to be involved in autonomic and emotional/aversive aspects of pain.