Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint

Abstract

Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies.Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration. Systemic administration of the CB2 receptor agonist JWH133 attenuated OA-induced pain behaviour, and the changes in circulating pro- and anti-inflammatory cytokines exhibited in this model. Electrophysiological studies revealed that spinal administration of JWH133 inhibited noxious-evoked responses of spinal neurones in the model of OA pain, but not in control rats, indicating a novel spinal role of this target. We further demonstrate dynamic changes in spinal CB2 receptor mRNA and protein expression in an OA pain model. The expression of CB2 receptor protein by both neurones and microglia in the spinal cord was significantly increased in the model of OA. Hallmarks of central sensitization, significant spinal astrogliosis and increases in activity of metalloproteases MMP-2 and MMP-9 in the spinal cord were evident in the model of OA pain. Systemic administration of JWH133 attenuated these markers of central sensitization, providing a neurobiological basis for analgesic effects of the CB2 receptor in this model of OA pain. Analysis of human spinal cord revealed a negative correlation between spinal cord CB2 receptor mRNA and macroscopic knee chondropathy.These data provide new clinically relevant evidence that joint damage and spinal CB2 receptor expression are correlated combined with converging pre-clinical evidence that activation of CB2 receptors inhibits central sensitization and its contribution to the manifestation of chronic OA pain. These findings suggest that targeting CB2 receptors may have therapeutic potential for treating OA pain.

Compensatory Activation of Cannabinoid CB2 Receptor Inhibition of GABA Release in the Rostral Ventromedial Medulla in Inflammatory Pain

“…One key variable in these studies may be age of animals that are used for recording as we have previously reported a marked decrease in GABA release probability between neonatal and adult RVM neurons that is the result of increased endocannabinoid tone in the adult rat RVM (Li et al, 2015). Other laboratories have also observed important differences in the function of the RVM between neonatal and adult rats (Hathway et al, 2009(Hathway et al, , 2012. We focused our studies on adult rats to understand modulation of endocannabinoid signaling in the RVM during persistent inflammation.…”

“…The analysis of tissue endocannabinoids was developed adapting methods previously described (Richardson et al, 2007;Chen et al, 2009;Zhang et al, 2010). Briefly, RVM slices were weighed and placed into 13 ϫ 100 mm screw-top silanized glass tubes, and 100 l of 0.02% trifluoroacetic acid was added.…”

“…More recently, numerous functional and anatomical evidence suggests that CB2 receptors are expressed in the nervous system (for review, see Atwood and Mackie, 2010). Both receptors are implicated in analgesic actions of cannabinoids Jayamanne et al, 2006;Anderson et al, 2014), and CB2 receptors are dramatically upregulated in the spinal cord and periphery in inflammatory (Beltramo et al, 2006;Burston et al, 2013) and neuropathic (Ibrahim et al, 2003;Zhang et al, 2003;Sagar et al, 2005;Guindon and Hohmann, 2008) pain models. CB2 receptors also play an important role in inhibiting chemotherapy-induced neuropathic pain (Rahn et al, 2008;Deng et al, 2015a).…”

“…Endocannabinoids are synthesized in neurons in response to activation of postsynaptic neurons, released and act as retrograde messengers to inhibit presynaptic neurotransmitter release (Kreitzer and Regehr, 2002;Wilson and Nicoll, 2002). CB1 and CB2 receptor inhibitors block endocannabinoid signaling in both central and peripheral sites, promoting and/or prolonging hyperalgesia (Richardson et al, 1997;Calignano et al, 1998;Meng et al, 1998), indicating that these receptors are potential targets for novel analgesic drugs.…”

The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease

“…The tonic release of spinal endocannabinoid levels counteract peripheral sensitization through enhanced endocannabinoid signaling within the spinal cord (42). In a rat model of OA pain, systemic administration of CB2 agonist, JWH-133, suppressed pain behavior, while acute administration to the spine inhibited mechanically stimulated noxious neurotransmission (43).…”