Nonnociceptive afferent activity depresses nocifensive behavior and nociceptive synapses via an endocannabinoid-dependent mechanism

Abstract

Previously, low-frequency stimulation (LFS) of a nonnociceptive touch-sensitive neuron has been found to elicit endocannabinoid-dependent long-term depression (eCB-LTD) in nociceptive synapses in the leech central nervous system (CNS) that requires activation of a presynaptic transient receptor potential vanilloid (TRPV)-like receptor by postsynaptically synthesized 2-arachidonoyl glycerol (2-AG). This capacity of nonnociceptive afferent activity to reduce nociceptive signaling resembles gate control of pain, albeit longer lasting in these synaptic experiments. Since eCB-LTD has been observed at a single sensory-motor synapse, this study examines the functional relevance of this mechanism, specifically whether this form of synaptic plasticity has similar effects at the behavioral level in which additional, intersegmental neural circuits are engaged. Experiments were carried out using a semi-intact preparation that permitted both synaptic recordings and monitoring of the leech whole body shortening, a defensive withdrawal reflex that was elicited via intracellular stimulation of a single nociceptive neuron (the N cell). The same LFS of a nonnociceptive afferent that induced eCB-LTD in single synapses also produced an attenuation of the shortening reflex. Similar attenuation of behavior was also observed when 2-AG was applied. LFS-induced behavioral and synaptic depression was blocked by tetrahydrolipstatin (THL), a diacylglycerol lipase inhibitor, and by SB366791, a TRPV1 antagonist. The effects of both THL and SB366791 were observed following either bath application of the drug or intracellular injection into the presynaptic (SB366791) or postsynaptic (THL) neuron. These findings demonstrate a novel, endocannabinoid-based mechanism by which nonnociceptive afferent activity may modulate nocifensive behaviors via action on primary afferent synapses.

Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by Aβ-fiber stimulation

“…31,45,62,65 Intriguingly, in invertebrates such as the medicinal leech, activities in nonnociceptive afferents depress transmission of nociceptive inputs converging onto the same postsynaptic neuron through endocannabinoid-dependent mechanisms. 61,63 However, this mechanism has not been examined in mammals. In addition to different stimulation protocols, neuroanatomy, and neurochemistry, the depression of C-eEPSCs in mouse SG neurons after Aβ-ES is fundamentally different from that in leeches.…”

“…6,11,62,65 Intriguingly, stimulation of nonnociceptive afferents may induce endocannabinoid-dependent suppression of nociceptive transmission in invertebrates. 61,63 CB1 receptors are expressed in neurons and astrocytes, whereas CB2 receptors are expressed mostly in microglia and macrophages. 8,31,47 Although endocannabinoid activation of CB1 receptors generally leads to neuronal and pain inhibition, 31,64,65 it may also facilitate pain transmission and potentially contribute to heterosynaptic pain sensitization induced by C-fiber inputs.…”

Cannabinoid Receptor Type 1 Antagonist, AM251, Attenuates Mechanical Allodynia and Thermal Hyperalgesia after Burn Injury

“…1–4 Pain-related cannabinoid receptors are of two types, cannabinoid receptor 1 and 2 (CB1R and CB2R), and are located in the central and peripheral nervous systems. 3–6 Exogenous cannabinoid agonists have been used to attenuate pain responses in several pain models including inflammatory and neuropathic pain.…”

Cannabinoids Occlude the HIV-1 Tat-Induced Decrease in GABAergic Neurotransmission in Prefrontal Cortex Slices

“…Upregulation of the endogenous cannabinoids N-arachidonoyl ethanolamine (anandamide; AEA) and 2-arachidonoyl glycerol (2-AG) have protective properties in neurodegenerative disorders, including multiple sclerosis, Parkinson, and Alzheimer disease models (Grant and Cahn, 2005; Scotter et al, 2010; Maroof et al, 2013; Pertwee, 2014; Xu and Chen, 2015). Endocannabinoids act predominantly via cannabinoid 1 (CB 1 ) and/or cannabinoid 2 (CB 2 ) receptors, although involvement of transient receptor potential (TRP) channels (Higgins et al, 2013; Yuan and Burrell, 2013; Kano, 2014) and/or other G-protein-coupled receptors (GPCRs) (Chevaleyre et al, 2006; Harkany et al, 2008; Ross et al, 2012) have been reported. CB 1 receptors (CB 1 Rs) are the most abundant G-coupled receptors in the brain, with the highest concentration in regions such as the cortex, hippocampus, and basal ganglia (Matsuda et al, 1990).…”