Chiropractic + Naturopathic Doctor • July/August 2022 • The intersection of spinal manipulation and the ECS

In Part 1 of this series (MAY-JUNE 2022), I discussed the role of the endocannabinoid system (ECS) in inflammatory and neuropathic pain models and the potential of targeting the ECS to generate an analgesic effect. Recall that cannabinoid receptor agonists, endocannabinoid-regulating enzyme inhibitors, and other pharmacological strategies to manipulate the endogenous cannabinoid system can decrease abnormally heightened sensitivity to pain (hyperalgesia) and allodynia found in a diverse range of inflammatory and neuropathic pain states. Clinical studies consistently demonstrate efficacy of cannabis and cannabinoid receptor agonists in reducing neuropathic pain states in humans, but adverse effects associated with use of medical cannabis (specifically THC) as well as challenges in ensuring standardized formulations have resulted in limited uptake by health care professionals and patients. There is, however, a growing body research that has identified numerous non-cannabis compounds and other constituents of cannabis aside from THC, that have therapeutic efficacy and are in common use.

Plants have been the predominant source of medicines throughout most of the human history and remain so today outside of industrialized societies. Investigations of Cannabis, with its diverse phytochemistry, has resulted in the discovery of the unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom, that only cannabis harbored active agents affecting the endocannabinoid system, more recent research has identiﬁed numerous additional plants whose components stimulate, antagonize, or modulate different aspects of the endocannabinoid system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others.1

As a naturopathic doctor, I am familiar with many of these compounds and have used them frequently without fully realizing that I was modulating the EC. The same is true for chiropractic practice.

To review, the endocannabinoid system (ECS) is a lipid signalling network in which arachidonic acid (AA) derived lipids act in concert with specific receptors and enzymes resulting in the complex modulation of numerous physiological and pathophysiological processes. The ECS consists of receptors, specifically the cannabinoid receptors, CB1,CB2 and suspected third receptor, GPR55. These receptors are differentially activated by the endocannabinoids, 2-arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine (AEA also referred to as anandamide). AEA and 2-AG, modulate different ion channels and nuclear receptors, including transient receptor potential vanilloid 1 (TRPV1), GABAa receptors and PPAR-Y . The final component of the ECS included the enzymes responsible for degrading the EA and 2-AG, namely, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These enzymes have been shown to regulate local and paracrine EC concentrations and are important targets for therapy.2

Endocannabinoids are act as a brake on neuronal hyperactivity, being produced in response to high levels of stimulation and feeding back negatively on the circuit through interaction with pre-synaptic cannabinoid receptors. In pain pathways, these actions produce analgesia by inhibiting the transmission of pain signals.

There are two main types of physical pain, nociceptive pain, and neuropathic pain. Nociceptive pain is the most common type, caused by potentially harmful stimuli being detected by nociceptors around the body. Nociception refers to the central nervous system (CNS) and peripheral nervous system (PNS) processing of noxious stimuli, such as tissue injury and temperature extremes, which activate nociceptors and their pathways. Pain is the subjective experience one feels because of the activation of these pathways. However, this perception depends on the action potential frequency, the time interval in between each action potential, and input from higher-order brain centers. The receptors responsible for relaying nociceptive information are termed nociceptors. They can be found on the skin, joints, viscera, and muscles. A wide variety of chemical substances activate these receptors, including globulin and protein kinases, arachidonic acid, histamine, nerve growth factor, substance P, calcitonin gene-related peptide (CGRP), potassium, serotonin, acetylcholine, low-pH solutions, ATP, and lactic acid. Receptors are also activated by temperature extremes, high pressures, and tissue damage causing inflammation.

Nociceptive pathways begin with the transduction of a noxious stimulus, such as mechanical pressure, into action potentials by a specialised class of sensory afferent neurones in the periphery (e.g. mechanoreceptors in the skin). Action potentials travel via the axon of the primary afferent neurone, past the cell body located in a dorsal root ganglion, to a synapse in the superﬁcial dorsal horn of the spinal cord. Following the integration of inputs from multiple cell types within the spinal cord, these action potentials will then pass up one of several ascending pathways to the brainstem, and subsequently to the thalamus, which then relays the signal to higher brain regions involved in the sensory (e.g. the somatosensory cortex) and emotional/affective (e.g. the amygdala and cingulate cortex) aspects of pain. There is signiﬁcant crosstalk between supra-spinal nociceptive regions, and nociceptive signals can be ampliﬁed or dampened by descending modulatory pathways projecting from the brain to the spinal cord.3

Systemic administration of cannabinoid receptor ligands is well known to produce analgesia in animal models of acute and chronic pain; however, concerns remain over dependence, tolerance, and the cognitive side effects produced by these medications. The undesirable effects of cannabinoids are caused by the global activation of CNS CB1 receptors.3–5 The mechanism is likely multifaceted, involving inhibition of the production and release of proinﬂammatory and pronociceptive mediators such as reactive oxygen species and cytokines by peripheral immune cells and the peripheral release of endogenous opioids. Since ECs are rapidly degraded, their effects are shortlived, and they are thus unsuitable for use as analgesics. However, the recent development of speciﬁc inhibitors of the major catabolic enzymes (MAGL and FAAH) has enabled researchers to prolong the effect of endogenously generated ECs. This is a very promising analgesic strategy, since ECs are speciﬁcally generated at sites of nociceptive activity, and such an approach may avoid the unwanted effects of global CB1 receptor agonism.4

Spinal manipulation (SM) generally consists in the application of a mechanical force on spinal joints in the form of a high velocity and low amplitude thrust preceded by a slower preload phase. Both the preload and thrust phases impact paraspinal muscle responses and load articular tissues, including the intervertebral discs, joint capsules, and ligaments. Previous studies suggest that the mechanical force applied during SM alters spinal biomechanics and activates paraspinal sensory terminals. It has been proposed that this afferent fibre stimulation initiates a cascade of peripheral and central neurophysiological effects.6

Previous studies on pain relief by SM have reported effects on the peripheral nervous system, spinal cord mechanisms and supraspinal processes. I would suggest that the peripheral mechanisms of spine pain are the point of intersection with the endocannabinoid system. In acute and chronic inflammatory states, spine pain may be modulated by the sensitization and desensitization of nociceptors by pro- and anti-inflammatory mediators. SM may produce pain relief by modulating inflammatory processes and sensitization in peripheral tissues.6

Peripheral substance P (SP) is a neurotransmitter of nociceptive afferent nerves in the somatic nervous system and in synaptic terminals of the spinal dorsal horn. SP effects are mediated through three different neurokinin (NK) receptors: NK-1, NK-2, and NK- 3. The NK-1 receptor has a strong affinity for SP. SP-induced activation of NK-1 receptors facilitates the processing of noxious information within the spinal cord and is involved in inflammation and neuropathic pain.

Transient receptor potential vanilloid subtype 1 (TPRV1) is specifically expressed by the nociceptors of C fibers and has an important role in triggering hyperalgesia by reacting to capsaicin, noxious heat, photons, and various endogenous ligands. TRPV1 activity is enhanced by inflammatory mediators such as nerve growth factor, somatostatin, bradykinin, prostaglandins, and serotonin, suggesting that TRPV1 is essential for the integration of various signaling pathways that mediate sensitivity to stimuli.

SP is involved in the hypersensitization of inflammatory pain by activating NK-1 expressed by nociceptive neurons and potentiating the activity of TRPV1 upon peripheral inflammation. This suggests that the activation of NK-1 receptors by peripheral SP increases TRPV1 sensitivity and triggers hyperalgesia. 7

Following cervical SM, an increase in plasmatic substance P was reported, while pressure- pain sensitivity decreased. It was proposed that the augmented substance P may underlie the hypoalgesic effects of SM, based on previous reports showing that substance P can inhibit nociceptive transmission in the spinal cord via feedforward mechanisms. However, this contrasts with the large body of evidence that describes substance P as a pro-nociceptive neuromodulator. Peripheral inflammation and tissue injury are associated with a release of substance P. In turn, substance P is involved in neurogenic inflammation, hyperalgesia, and allodynia. Both its peripheral and central release by primary afferents seems to be essential to experience moderate to intense pain. Also, elevated cerebrospinal fluid levels of substance P were observed in patients with chronic pain, likely reflecting levels in the spinal cord.

Cytokines and chemokines are immune regulatory substances that can induce inflammation and contribute to nociception. The endocannabinoid system sits at the crossroads of these 2 systems. Inflammatory cytokines Interleukin 1 beta and TNF-alpha are two important cytokines released by innate immune cells during inflammation and key signalling molecules between immune cells and nociceptor. Activation of cytokine receptors result in the activation of signal transduction pathways in sensory neurons leading to downstream activation of nociceptive TRP and voltage- gated channels. The resulting sensitization of nociceptors means that normally innocuous mechanical and heat stimuli can now activate nociceptors.8

In patients with LBP, pro-inflammatory mediators are involved in the sensitization of nociceptors and their inflammatory profiles vary depending on pain duration. Preliminary results suggest that SM may reduce pro- inflammatory responses, which in turn may produce pain relief through changes in peripheral inflammation and nociceptor sensitization. The current literature suggests that SM may reduce pro-nociceptive or pro- inflammatory mediators that are increased during spine pain.6

Recall from Part 1 of this series that endogenous cannabinoids (Anandamide and 2-AG) are enzymatically regulated, produced, and released on demand. These endocannabinoids activate CB1 and CB2 receptors. Another important pathway involves the binding of Anandamide which activates Transient receptor potential vanilloid subtype1 (TRPV1). Desensitization of nociceptive neurons to TRPV1 agonists (e.g., capsaicin) as an alternative pharmacological approach to block pain in the periphery where it is generated.9

TRPV1 agonists fall into two classes, the pungent or caustic substances (capsaicin, piperine), and those that are non-irritating (CBD). While the former substances cause pain upon application, continued exposure to TRPV1 agonists cause conformational change in the receptor and a refractory state due to desensitization of the receptor, making them functional antagonists upon chronic application.1

Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study as well as other phytotherapeutic agents, the cannabis terpenoids, that display unique therapeutic effects that may contribute meaningfully to what has been referred to and the entourage effect of cannabis- based medicinal extracts. The entourage effect has been found to play an important role in the effectiveness of different cannabis formulations with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections.10

The therapeutic efficacy of cannabis products comes with a risk of toxicity and high abuse potential due to the psychoactivity of THC so there is a demand for alternative compounds combining similar effects with a robust safety profile and regulatory approval. Palmitoylethanolamide (PEA) is an endocannabinoid- like lipid mediator, primarily known for its anti-inflammatory, analgesic, and neuroprotective properties. It appears to have a multi-modal mechanism of action, by primarily activating the nuclear receptor PPAR-Y while also potentially working through the ECS, thus targeting similar pathways as CBD. With proven efficacy in several therapeutic areas, its safety and tolerability profile and the development of formulations that maximize its bioavailability, PEA is a promising alternative to CBD.11

Palmitoylethanolamide (PEA) is a an endogenous biologically active lipids and a relative of the endocannabinoid anandamide (AEA).12 Studies have found that PEA has antinociceptive properties mediated via CB1, PPARc and TRPV1 receptors, and that the most likely mechanism might be the so-called ‘‘entourage eﬀect” due to the PEA-induced inhibition of the enzyme catalyzing the endocannabinoid anandamide (AEA) degradation that leads to an enhancement of its tissue levels thus increasing its analgesic action. In addition, PEA might act through the modulation of local mast cells degranulation and signiﬁcantly reduces the production of many mediators such as TNFa and neurotrophic factors, like Nerve Growth Factor (NGF). PEA demonstrates anti- inﬂammatory properties, analgesic activity in acute and inﬂammatory pain and neuroprotection. In animal models, it signiﬁcantly relieves neuropathic pain in the partial sciatic nerve injury model in the rat.13

It is the ability of PEA to activate and modulate the transient receptor potential vanilloid receptor 1 (TRPV1) channels that accounts at least part of for anti-nociceptive effect.14,15

Furthermore, the analgesic action of PEA in conjunction with Acetaminophen, acts in a synergistic manner through the inhibition of the NF-KB pathway, which leads to a decrease of cyclooxygenase 2-dependent prostaglandin E2(COX-2/PGE2) release.16

Although the exact mechanism through which acetaminophen exerts its effects has yet to be fully determined, acetaminophen may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspar tate (NMDA) and substance P, resulting in elevation of the pain threshold. 18