The cannabinoid system and pain

Abstract

Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB₁receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".

Keywords: AA-5-HT (PubChem CID: 10027372); Amygdala; BIA-102474 (PubChem CID: 46831476); Cannabinoid; Cortical control of pain; Endocannabinoid; FAAH; JZL184 (PubChem CID: 25021165); JZL195 (PubChem CID: 46232606); MAGL; MJN110 (PubChem CID: 71722059); PF-04457845 (PubChem CID: 24771824); Pain; Stress; Stress-induced analgesia; Stress-induced hyperalgesia; URB597 (PubChem CID: 1383884); URB937 (PubChem CID: 53394762); mGluR5; mPFC.

Figure 1. Schematic of Nociceptive Pathways & Sites of EC System Expression

Nociceptive stimuli are conducted from the periphery to the dorsal horn of the spinal cord, and then transmitted to the supraspinal regions via the spinothalamic tract (STT, $\mathbf{blue}$) and spinoparabrachial tract (SPBT, $\text{red}$). The major descending modulatory control pathway (DMCP, $\mathbf{purple}$) is displayed on the right. This pathway crosses the midline at the level of the medulla. Coloured areas indicate the position of synapses, and therefore sites of additional neuronal processing and endocannabinoid signalling, in each pathway. The positions of laminae I–VI in the dorsal horn are indicated by dotted lines, while the black region in the brain represents the lateral ventricles. Thal., thalamus; VMH, ventromedial hypothalamus; PbN, parabrachial nucleus; PAF, primary afferent fibre; PAG, periaqueductal grey matter; RVM, rostroventral medulla; Pyr., pyramidal tract; DRG, dorsal root ganglion. Adapted from (Hunt and Mantyh, 2001).

Figure 2. Schematic of mGLuR5-CB₁ coupling in mPFC-amygdala interaction in pain states

The amygdala $(\text{green dashed box})$ sends glutamatergic (Glu) projections from the basolateral nucleus, (BLA) to mPFC $(\text{blue dashed box})$ pyramidal cells activating mGluR5, and to mPFC GABAergic interneurons inhibiting mPFC pyramidal cells (“feedforward inhibition”). mGluR5 couples to 2-AG synthesis via DAGLα. 2-AG release acts on presynaptic CB₁ to inhibit synaptic inhibition hence increasing mPFC output. mPFC pyramidal cells send glutamatergic projections to GABAergic interneurons in the amygdala (intercalated cells, ITC) to control amygdala output from the central nucleus (CeA).