doi.org/10.36721/PJPS.2020.33.1.REG.229-239.1 REVIEW The nicotinic modulation of pain Nurcan Bektas*, Dilara Nemutlu, Mevcude Cam, Yagmur Okcay, Hazal Eken and Rana Arslan Anadolu University Faculty of Pharmacy, Department of Pharmacology, Eskisehir Turkey Abstract: Pain is a physiological unpleasant sensation that associated with actual or potential tissue damage and affects the major part of human population. Numerous modulatory system control pain through a complex process. The drugs that regulate the modulators involving in this process are currently available; however, the studies to understand the process and develop new agents are still going on. In this review, it is aimed to relay information about how nicotinic receptors contribute the pain modulation. It is obvious that a wide variety of nicotinic receptors is located in both peripheral and central areas. Among these receptors α7, α4β2 and α9α10 receptor subtypes draw attention in terms of pain modulation. The fact that different receptor subtypes involve in different processes of different pain conditions leads to provide beneficial results from the agonism of α7, α4β2 and antagonism of α9α10. The major restraint of the usage of nAChR agonists is their adverse effects. However, nowadays, the side effects are reduced by the clinical developments. Additionally, positive allosteric modulators that amplify the effectiveness of nAChR ligands are in demand. Keywords: Analgesia; nicotinic receptors; positive allosteric modulators. INTRODUCTION these pain modulation pathways, hence it may explain why nicotinic receptor ligands acting as analgesic are International Association for the Study of Pain (IASP) effective in both acute and chronic pain conditions. describes pain as an unpleasant sensory and emotional nAChRs are transmembrane channels with numerous experience arising from any part of the body and subtypes (Molas and Dierssen, 2014). Because different associated with actual or potential tissue damage, or nAChR subtypes assume different roles in pain described in terms of such damage. The pain is an modulation, sometimes agonism is beneficial while ‘experience" and in this respect it differs from sometimes antagonism is advantageous. More recently ‘nociception'. Nociception is called a neural process allosteric modulators other than orthosteric ligands are provides transduction and transmission of a noxious more in demand. Allosteric modulators bind to the stimulus to the brain by using pain pathways (Merskey receptor at a site other than the orthosteric ligands bind and Bogduk, 1994; Steeds, 2009). The pain may and lead a conformational change (Neubig et al., 2003). demonstrate acute or chronic characteristic depend on the Positive allosteric modulators of nAChRs contribute the underlying pathogenesis. Acute pain begins suddenly and analgesia that induced by nAChR activation via probably has limited duration (Macintyre et al., 2010) maintaining the cholinergic tone (Uteshev, 2014). while the chronic or persistent pain can be described as continuous or repeating pain, lasting the outside limits of In this review, the nicotinic side of the pain modulation is the typical progress of acute disease, more than 3 to 6 discussed. The experimental studies are examined to months. Chronic pain pathophysiology comprises two answer how nAChRs involve in this modulation. categories as nociceptive or neuropathic (Feinberg et al., 2013). Since different mechanisms role in the Nicotinic receptors in pain modulation pathophysiology of acute and chronic pain and even Cholinergic receptors that are located in the autonomic nociceptive and neuropathic pain, it is possible that all the ganglion and striated muscle cells are called as nAChR. drug classes may not relieve all pain types. Modulation of nAChRs are divided into two groups as ‘neuron type’ and pain is a highly complex process involving various ‘muscle type’ because they are blocked by different mediators and receptors over an extensive network from antagonists. Neuronal nAChRs are blocked by the periphery to the central nervous system (CNS). The hexamethonium and its analogs, muscle type nAChRs are rate of participation of the chemicals and receptor types in blocked by decamethonium and skeletal muscle relaxants the modulation depend on the pain types and noxious like it (Taylor, 1996). nAChRs are transmembrane stimulus. It is clear that the nicotinic receptors (nAChR) channels that belong to the "Cys-loop” superfamily which discussed in this review, participate in many of (Molas and Dierssen, 2014). The nAChRs involving in pain modulation are neuronal type nAChRs, and all the *Corresponding author: e-mail: [email protected] Pak. J. Pharm. Sci., Vol.33, No.1, January 2020, pp.229-239 229 The nicotinic modulation of pain mentioned nAChRs in this review are neuronal type study, the role of ventral hippocampal nAChRs in stress- nAChRs. Presently, it is known that nine α (α2- α10) and induced analgesia in mice were assessed by intra- ventral three β (β2–β4) subunits exist (Kalamida et al., 2007). The hippocampal microinjection of nicotine (enhancement of α5 and β3 subunits are considered to be ‘modulatory’ stress-induced analgesia) and mecamylamine (prevention subunits because they do not form functional receptors of stress-induced analgesia) and. When the results were when expressed alone or when expressed as the sole α or β evaluated in the tail flick test, it is deduced that exposure to subunit in heteromeric channels (Vincler, 2005). acute stress induces stress-induced analgesia time- Additionally, nAChRs could be examined under two dependently and the ventral hippocampal cholinergic classes: (a) the high-affinity agonist binding class, which system may be involved in stress-induced analgesia via do not bind α- bungarotoxin (α-bgtx), later investigated to nAChRs. be the heteromeric nAChRs formed by α2-α6 and β2-β4 subunits; and (b) a second class that binds agonists with μm The investigations direct the α7 and α4β2 as nAChRs affinities and binds α-bgtx with nm affinities, later shown subtypes because of their distribution in neuronal to be generally homomeric molecules formed by α7–α9 pathways and their involvement in pain modulation. subunits (Kalamida et al., 2007). These subtypes are primarily present in CNS pain pathways as well as the periphery. There is evidence for The presence of nAChRs seems to be nearly omnipresent nAChR expression on both DRG and trigeminal ganglion in pain pathways. They are found in primary afferents, neurons. DRG neurons predominantly express α7 spinal cord excitatory and inhibitory interneurons and nAChRs (Genzen, et al., 2001). α7 nAChRs are also projecting neurons, the medial habenula and in brain expressed on macrophages and immune cells and nuclei with descending spinal projections. However, their contribute to peripheral and central antinociception (De expression is not homogeneous between these populations Jonge and Ulloa, 2007). α4β2 subunits are located of neurons, nor is the expression uniform within each of extensively in the central and peripheral nervous system. the aforementioned groups. nAChRs, whose roles in The anatomical distribution of α4β2 nAChRs in the brain nicotine addiction and autonomic physiology are well and the spinal cord strengthen the role of this receptor in known, also have significant analgesic effects on animal nociceptive transmission (Nirogi et al., 2013). There are models and humans (Vincler, 2005). The nicotine that also α3- and β4-containing subtypes that are principally stimulates neurons on the descending inhibitory pain highly expressed in the autonomic ganglia, and are also pathways by activating the neurons in the subcortical area expressed in subsets of neurons in the brain (Picciotto et of the brain and revealing ACh secretion possesses weak al., 2001). antinociceptive character (Arneric, 2000). The effect of nicotine is completely antagonized by injection of It has been observed that the residual nicotine-induced antagonists' combinations, not by a single antagonist. analgesia remained in α4-subunit knockout (KO) mice. Thereby, it is thought that multiple descending inhibitory This data reveals a role for non-α4-containing receptors pathways are involved in antinociception induced by such as α3- and β4-subunits (Marubio et al., 1999). nicotine (Decker and Meyer, 1999). According to another However, a recent study demonstrated that α3β4 nAChRs view, the stimulation of spinal cord by activation of do not significantly take part in mediating antinociception nAChRs may also lead antinociception via increasing after acute nicotine and AuIB, a selective α3β4 intracellular Ca++ (Arneric, 2000). antagonist, administration (Jackson et al., 2013). The α5 subunits that are incorporated with α4β2, α3β4, or α3β2 nAChRs are found in the periphery including macrophages, nAChR subtypes, do not shape functional receptors alone, immune cells and in the CNS including many areas they could only significantly alter the properties of the contributing to pain such as ascending and descending channel (Umana et al., 2013). It was reported that α5 nociceptive pathways, spinal cord dorsal horn (DH) and in nAChRs are involved in nicotine-mediated sensory nerve afferents (AlSharari et al. 2013; Umana et antinociception because α5 KO mice remain sensitive, al. 2013; Tracey, 2002). While there is a great deal of even a little, to nicotine induce antinociception (Jackson studies about the roles of nAChRs in these areas, it is et al., 2010). continued to elucidate