**The Involvement of Purinergic System in Pain: Adenosine Receptors and Inosine as Pharmacological Tools in Future Treatments**

Francisney Pinto Nascimento1,2,

Sérgio José Macedo Jr.2 and Adair Roberto Soares Santos1,2 *1Department of Pharmacology; 2Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences; Universidade Federal de Santa Catarina Brazil* 

#### **1. Introduction**

 During the recent years, the interest in the purinergic system has been gaining importance, and this interest is not accidental. The purinergic system is so far known to be involved in several physiological conditions in mammals, becoming a potential therapeutic target for the treatment of many pathologies and disorders. One of the physiological roles is the control of pain. This chapter will emphasize adenosine receptors (P1) and its activation and inhibition by adenosine and by specific agonists or antagonists in the treatment of pain. Although most of the studies quoted in this chapter were performed in animals, in this chapter we will use the expression *analgesia* instead of *antinociception* (term used to report pain in animals) to simplify our communication. Some drugs that act on adenosine receptors have presented interesting results in clinical studies of pain and other drugs are under investigation. Of note, it has recently been shown that inosine, a metabolite of adenosine, has significant analgesic effects in several pre-clinical models of pain. Thus, the inosine can be an important tool in this area of study or even a molecule of interest for future pharmacological approaches, knowing that such as adenosine, it is produced endogenously and devoid of side effects in normal doses. In addition, new approaches using enzyme inhibitors of the purinergic system or supplies of adenosine suggest alternatives to potentiate and lasting analgesic effects of adenosine or analogs. Moreover, the release of purines and the adenosine A1 receptor activation are essential to analgesia by acupuncture in mice. Thus, purinergic system will be the target of many future pain-treatment researches. After all, it is indispensable to students and biomedical professionals to know and understand basic concepts about this endogenous system.

#### **2. Involvement of purinergic system in pain**

#### **2.1 Purinergic receptors: History and involvement in pain**

Purinergic receptors history began when Drury and Szent-Györgi described the potent actions of purines adenine and adenosine on the heart and blood vessels (Drury & Szent-

The Involvement of Purinergic System in Pain:

**3. Adenosine receptors and pain** 

**3.2 Distribution of adenosine receptors** 

**3.1 Adenosine receptors** 

(Burnstock, 2008).

Adenosine Receptors and Inosine as Pharmacological Tools in Future Treatments 629

Fig. 2. Total of publications with keywords ATP, Adenosine (Ado), Adenosine Receptors

Adenosine is the natural ligand of P1 receptors, also called adenosine receptors. All these receptors are G-protein coupled and are divided according to pharmacological, biochemical and molecular properties into four subtypes: A1, A2A, A2B and A3. Each receptor has a distinct distribution and due to its special features, has distinct roles as well (Burnstock et al., 2011; Fredholm et al., 2011; Ralevic & Burnstock, 1998; Ribeiro et al., 2002; Sawynok & Liu, 2003). Adenosine receptors were cloned and characterized in several mammal species

Adenosine receptors are present in several species and in distinct tissues. However, their distribution is quite irregular and different among species and mainly among tissues (Fredholm et al., 2011). A1 receptor (A1R) is a ubiquitous receptor. In the central nervous system, it is distributed in the cerebellum, cerebral cortex, hippocampus, thalamus, spinal cord (substantia gelatinosa), brain stem, olfactory bulb and other central sites. Peripherally A1R distribution is less wide than centrally, but there is a considerable density of A1R in sensory afferent fibers, mainly on C-fibers which are responsible for receiving and conducting the painful stimuli (Dixon et al., 1996; Sawynok, 2009). A2A receptor (A2AR)has an even distribution between central and peripheral nervous system, but mainly in central structures as nucleus accumbens, putamen, caudate and in immune tissues, vascular smooth muscle, endothelium, platelets and sensory neurons (Dixon et al., 1996; Fredholm, 1995; Ralevic & Burnstock, 1998; Sawynok, 2009). A2B receptor (A2BR) is also a ubiquitous receptor and it has been found either in many central or peripheral tissues. However, A2BR density is

(AdoR) and Inosine (Ino) plus Pain from 1930 until 2010. Source: Pubmed

Györgi, 1929). Later, in 1970 Burnstock presented evidence that ATP acted as a neurotransmitter in nonadrenergic noncholinergic (NANC) nerves supplying the gut, and finally, in 1972, the purinergic neurotransmission hypothesis was proposed (Burnstock, 1972). With these discoveries, the number of publications involving ATP and its metabolites grew quickly and continues to do so (Figure 1).

Fig. 1. Total of publications with keywords ATP, Adenosine (Ado), Adenosine Receptors (Ado Rec) and Inosine (Ino) from 1930 until 2010. Source: Pubmed

Afterwards, it was established that the ATP acted as a cotransmitter with classical transmitters in both the peripheral nervous system and in the central and that purines are also powerful extracellular messengers to non-neuronal cells (Burnstock & Knight, 2004). Burnstock, in 1978, provided the basis for the distinction of two classes of purinergic receptors; adenosine-sensitive P1 and ATP-sensitive P2 receptor classes. In 1985, Burnstock and Kennedy proposed a basis for distinguishing two types of P2 purinoceptors, namely, P2X and P2Y. Afterwards, in 1994 Abbracchio and Burnstock through studies of transduction mechanisms and cloning of both P2X and P2Y receptors put forward a new nomenclature system, naming them, P2X ionotropic ligand-gated ion channel receptors and P2Y metabotropic G protein-coupled receptors, respectively. Currently, seven subtypes of P2X receptors (P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7) and eight subtypes of P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, P2Y14) are clearly established. P2X and P2Y receptor activation by ATP stimulates cellular excitability, augments the release of excitatory amino acids, and consequently initiates pain responses (Burnstock, 2007; Burnstock & Williams, 2000). In the context of pain neurotransmission, preclinical studies show us that activation of P1 receptors by adenosine decreases pain, inflammation, and cellular excitability (McGaraughty & Jarvis, 2006). During the 80's and 90's research evaluating purinergic system in pain rocketed (Figure 2).

Fig. 2. Total of publications with keywords ATP, Adenosine (Ado), Adenosine Receptors (AdoR) and Inosine (Ino) plus Pain from 1930 until 2010. Source: Pubmed
