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Opioid and Endocannabinoid System in Orofacial Pain

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Opioid and Endocannabinoid System in Orofacial Pain Physiol. Res. 68: 705-715, 2019 https://doi.org/10.33549/physiolres.934159 REVIEW Opioid and Endocannabinoid System in Orofacial Pain M. ZUBRZYCKI1, M. STASIOLEK2, M. ZUBRZYCKA3 1Department of Cardiovascular and Thoracic Surgery, University of Ulm, Ulm, Germany, 2Department of Neurology, Medical University of Lodz, Lodz, Poland, 3Department of Cardiovascular Physiology, Interdepartmental Chair of Experimental and Clinical Physiology, Medical University of Lodz, Lodz, Poland Received March 3, 2019 Accepted May 20, 2019 Epub Ahead of Print August 19, 2019 Summary Introduction Orofacial pain disorders are frequent in the general population and their pharmacological treatment is difficult and controversial. The therapy of pain is currently one of the Therefore, the search for novel, safe and efficient analgesics is challenges of modern medicine. Orofacial pain disorders an important but still elusive goal for contemporary medicine. In are frequent in the general population and their the recent years, the antinociceptive potential of endocannabi- pharmacological treatment is difficult and controversial noids and opioids has been emphasized. However, concerns for (Weiss et al. 2017). This is due in part to limited the safety of their use limit their clinical applications. the understanding of the pathophysiology of the pain possibility of modulating the activity of endocannabinoids by disorders that arise from the structures innervated by the regulation of their synthesis and/or degradation offers an trigeminal nerve. The additional reasons include the innovative approach to the treatment of pain. A rat model of paucity of animal models, which allow to evaluate the trigeminal pain, utilizing tongue jerks evoked by electrical tooth responsiveness of nociceptors the magnitude of pulp stimulation during perfusion of the cerebral ventricles with nociceptive reaction by measuring baseline and various neurotransmitter solutions can be used in the stimulated release of neuropeptides during the activation pharmacological studies of nociception in the orofacial area. The of trigeminal afferents (Hargreaves 2011, Zubrzycka and aim of this review is to present the effects of pharmacological Janecka 2002, Zubrzycka and Janecka 2011). activity of opioids and endocannabinoids affecting the In recent years, an accumulating body of transmission of the sensory information from the orofacial area evidence has suggested the potential use of on the example of trigemino-hypoglossal reflex in rats. endocannabinoids and opioids as the modulators of orofacial pain transmission (Zubrzycka et al. 2011, Key words Zubrzycka et al. 2017). Orofacial pain ● Opioid and cannabinoid receptors ● It has been demonstrated that the endogenous Endocannabinoid system ● Perfusion of cerebral ventricles ● opioid system could be involved in cannabinoid Trigemino-hypoglossal reflex antinociception and recent data have also provided evidence for a role of the endogenous cannabinoid system Corresponding author in opioid antinociception (Bushlin et al. 2010, Cichewicz M. Zubrzycka, Department of Cardiovascular Physiology, 2004, Wilson-Poe et al. 2013). Interdepartmental Chair of Experimental and Clinical Physiology, Opioids and cannabinoids produce antinoci- Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, ception through separate (although possibly interrelated) Poland. E-mail: [email protected] mechanisms (Cichewicz 2004, Roberts et al. 2006, Tham et al. 2005). PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) 2019 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 706 Zubrzycki et al. Vol. 68 They also exhibit overlapping neuroanatomical The opioid system distribution and comparable functional neurobiological properties (Nawarro et al. 2001). Both receptor types are The opioidergic system consists of opioid found in several brain regions known to participate in receptors and their peptide ligands. Opioid receptors were antinociception, including the periaqueductal central gray discovered approximately 40 years ago and they belong (PAG), raphe nuclei and central medial thalamic nuclei to the G-protein coupled receptor (GPCR) family. The (Cichewicz 2004, Manzanares et al. 1999). Furthermore, heterogeneity of opioid receptors and the existence of at μ- and CB1 receptors have been shown to colocalize to least three main opioid receptor types, designated as µ, δ the same neurons within the superficial dorsal horn of the and κ (or MOR, DOR and KOR, respectively) is widely spinal cord, the first site of synaptic contact for peripheral accepted (Kieffer 1995). Opioid receptors and nociceptive afferents, raising the possibility of direct endogenous opioid peptides are most abundant in the interactions between these receptor types on the same cell central nervous system (CNS) but are also localized in (Hohmann et al. 2005, Salio et al. 2001). many peripheral tissues of the mammalian organism Interestingly, CB1 receptors can exist as (Le Merrer et al. 2009). homodimers and they may also form heterodimers or Opioid receptors can be activated by exogenous oligomers with one or more other classes of co-expressed opiates, such as morphine and its derivatives, as well as GPCRs, in a manner that may lead to cross-talk between by endogenous opioid peptides: enkephalins (ENK), CB1 receptors and noncannabinoid sites (Pertwee 2006). dynorphins (DYN), β-endorphin (β-END) and Interactions between endocannabinoids (ECs) endomorphins (EMs), which are the family of and the opioid system during antinociception have been neurochemical messengers that exhibit high affinity for evaluated using cannabinoid receptor antagonists or one or more of the opioid receptors (Przewlocki and inhibitors of enzymes that degrade ECs. Studies showing Przewlocka 2001, Rokyta 2018). that treatment with cannabinoid receptor agonists can Opiates exert their antinociceptive activity by lead to opioid peptide release and that ECs are involved activation of the μ-opioid receptors. Therefore, the search in the actions of opioid agonists confirm the synergistic for natural and synthetic ligands of this receptor has interactions between these two receptor systems become an attractive goal. The discovery in 1997 of two (Cichewicz 2004, Lau et al. 2014a). endogenous ligands of the μ-opioid receptor, It is generally accepted that tooth pulp endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endo- stimulation in rats represents a valuable pain model and morphin-2 (Tyr-Pro-Phe-Phe-NH2), gave hope that they has been proposed as a model for trigeminal pain could be used as analgesics devoid of at least some of (Chapman et al. 1986). undesired side effects of morphine (Zadina et al. 1997). The trigemino-hypoglossal reflex has been used However, the use of endomorphins (EMs) as in research on the properties of neuropeptides perfused analgesics is of little therapeutic value because these through the cerebral ventricles. In this pain model, the peptides are quickly degraded by enzymes and have amplitude of the evoked tongue jerks (ETJ) induced by a very limited ability to penetrate the blood-brain barrier tooth pulp stimulation is recorded. The magnitude of ETJ (BBB) effectively due to their small size and hydrophilic during perfusion of the cerebral ventricles with the nature. To overcome the limited access of exogenously neurotransmitters under investigation can be a measure of administered EMs to the brain, numerous chemical the effect of these compounds on the neural structures modifications of their structure have been proposed. To (Zubrzycka et al. 1997, Zubrzycki et al. 2015). date, the structure of endomorphins has been modified by The pharmacology and molecular mechanisms the introduction of D-amino acids and unnatural amino of sensory transmission in the trigeminal system have not acids with L and D configurations, or by cyclization of been fully identified so far, which is associated with the the linear sequences (Perlikowska et al. 2014). lack of effective treatment for pain syndromes originating from the orofacial area. The endocannabinoid system Therefore, the aim of this review is to present the effect of pharmacological activity of opioids and The endogenous cannabinoid system (ECS), endocannabinoids affecting the transmission of sensory which consists of three principal components, i.e. information from the orofacial area on the example of “classical” cannabinoids (CB1, CB2) and “non-classical” trigemino-hypoglossal reflex in rats. (TRPV1, GPR55, PPARs) receptors, endogenous ligands 2019 Opioids and Endocannabinoids in Pain 707 (anandamide, AEA; 2-arachidonyloglycerol, 2-AG) and arachidonic acid and ethanolamine, as opposed to the enzymes, responsible for CB synthesis and degradation, amide linkage found in AEA. It acts as an antagonist of has recently attracted much attention as a crucial site in CB1 receptor and agonist of CB2 receptor. Other pain pathophysiology (Fonseca et al. 2013). Both CB1 important fatty acid amides related to endocannabinoids and CB2 receptors which are both GPCRs inhibit the are oleoylethanolamide (OEA), an agonist of the CB1 activity of adenylyl cyclase (Kaminski 1996) and activate receptor and palmitoylethanolamide (PEA), a selective mitogen-activated protein (MAP) kinases (Bouaboula CB2 receptor agonist (Di Marzo et al. 2001). et al. 1995). Additionally, CB1 (Mackie and Hille 1992) However, much attention has currently been and CB2 receptors
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