previous reports showing that substance P can inhibit nociceptive transmission in the spinal cord via feedforward mech-anisms. However, this contrasts with the large body of evidence that describes substance P as a pro-nociceptive neuro-modulator. Peripheral inflammation and tissue injury are associated with a release of substance P. In turn, substance P is involved in neurogenic inflamma-tion, 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 im-mune regulatory substances that can induce inflammation and contribute to nociception. The endocannabinoid system sits at the crossroads of these 2 systems. Inflammatory cytokines Inter-leukin 1 beta and TNF-alpha are two important cytokines released by innate immune cells during inflammation and key signalling molecules between im-mune cells and nociceptor. Activation of cytokine receptors result in the activa-tion of signal transduction pathways in sensory neurons leading to downstream activation of nociceptive TRP and volt-age-gated channels. The resulting sensi-tization of nociceptors means that nor-mally innocuous mechanical and heat stimuli can now activate nociceptors. 8 In patients with LBP, pro-inflamma-tory mediators are involved in the sen-sitization of nociceptors and their in-flammatory profiles vary depending on pain duration. Preliminary results sug-gest that SM may reduce pro-inflam-matory 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-noci-ceptive or pro-inflammatory mediators that are increased during spine pain. 6 Recall from Part 1 of this series that endogenous cannabinoids (Anan-damide and 2-AG) are enzymatically regulated, produced, and released on demand. These endocannabinoids acti-vate CB1 and CB2 receptors. Another important pathway involves the binding of Anandamide which activates Tran-sient receptor potential vanilloid www.Cndoctor.ca subtype1 (TRPV1). Desensitization of nociceptive neurons to TRPV1 agonists (e.g., capsaicin) as an alternative phar-macological approach to block pain in the periphery where it is generated. 9 TRPV1 agonists fall into two classes, the pungent or caustic substances (cap-saicin, 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 re-ceptor and a refractory state due to de-sensitization 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 re-cently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabi-noids, including tetrahydrocannabi-varin, cannabigerol and cannabi-chromene, exert additional effects of therapeutic interest. Innovative conven-tional plant breeding has yielded canna-bis 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 canna-bis-based medicinal extracts. The en-tourage effect has been found to play an important role in the effectiveness of different cannabis formulations with respect to treatment of pain, inflamma-tion, 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 de-mand for alternative compounds com-bining similar effects with a robust safety profile and regulatory approval. Palmi-toylethanolamide (PEA) is an endocan-nabinoid-like lipid mediator, primarily known for its anti-inflammatory, anal-gesic, and neuroprotective properties. It appears to have a multi-modal mecha-nism of action, by primarily activating PALMITOYLETHANOLAMIDE the nuclear receptor PPAR-Y while also potentially working through the ECS, thus targeting similar pathways as CBD. With proven efficacy in several thera-peutic areas, its safety and tolerability profile and the development of formu-lations 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-in-duced inhibition of the enzyme catalyz-ing the endocannabinoid anandamide (AEA) degradation that leads to an enhancement of its tissue levels thus increasing its analgesic action. In addi-tion, PEA might act through the modu-lation 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 an-ti-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 poten-tial vanilloid receptor 1 (TRPV1) chan-nels that accounts at least part of for anti-nociceptive effect. 14,15 Furthermore, the analgesic action of PEA in conjunction with Acetami-nophen, acts in a synergistic manner through the inhibition of the NF-KB pathway, which leads to a decrease of cyclooxygenase 2-dependent prosta-glandin 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 va-riety of neurotransmitter receptors in-cluding N-methyl-D-aspartate (NMDA) and substance P, resulting in elevation of the pain threshold. 18 For the full list of references, please visit cndoctor.ca/ECS-Part-2 July/August 2022 Chiropractic and Naturopathic Doctor 15
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