**1.3 Mechanism of action**

μ, δ, and κ opioid receptors are distributed in peripheral tissue as well as CNS. Stimulation of these receptors in the CNS results in analgesia, drowsiness, euphoria, a sense of detachment, respiratory depression, nausea and vomiting, depressed cough reflex, and hypothermia. When these receptors are stimulated in peripheral tissues, miosis, orthostatic hypotension, constipation, urinary retention etc. emerges.

After stimulation of these Gi/0-coupled opioid receptors, the adenylate cyclase enzyme is suppressed and the level of cyclic AMP decreases. In addition, the voltage-gated calcium channels in the axon ends or neuron soma are closed and intracellular calcium levels are reduced, potassium channels are opened and leading to an increase in potassium conductance. As a result, inhibition and hyperpolarization of neurons occurs when opioid receptors are stimulated [42, 43].

Analgesic or antinociceptive effects, which are indicated for use of opioids, develop at the level of the brain and spinal cord. At the brain level, attenuation of impulse spread is weakened and the perception of pain is inhibited, and at the spinal cord level, the transmission of pain impulses is suppressed [44].

#### **1.4 Opioid dependence**

Opioid dependence or addiction is a chronic, recurrent disease that changes neurotransmitter systems in the CNS and affects movement [45, 46]. Opioid dependence develops in both psychic and physical dependence. Physical opioid dependence occurs both when used for treatment and as a result of abuse. Opioid abuse is a relapsing disease with high morbidity and mortality, which is used at higher doses to produce the same effect due to tolerance. The higher the exposure time to opioids, the higher the degree of dependence and tolerance. After physical dependence develops, opioid consumption is maintained to prevent withdrawal symptoms. So the treatment is long and difficult. For this purpose, opioid agonists such as methadone, buprenorphine, an opioid antagonist naltrexone or abstinencebased treatment may be preferred. This disease, referred to as 'opioid abuse and opioid dependence' in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSMIV-TR), has been changed to 'opioid use disorder' in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [47].

The estimated annual prevalence of opioids in 2010 was 0.6–0.8% of the population aged 15–64 (26 <sup>10</sup><sup>6</sup> to 36 <sup>10</sup><sup>6</sup> ). The estimated annual prevalence of opioid use is between 0.3 and 0.5% of the adult population (13 <sup>10</sup><sup>6</sup> to 21 <sup>10</sup><sup>6</sup> past-year users) [48].

The mesocorticolimbic dopaminergic system, which project from the VTA to the NAc and medial prefrontal cortex (mPFC) are critically important in opioid dependence [49]. Opioids act on VTA and directly or indirectly cause an increase in dopamine release in NAc region [50]. In the pathogenesis of opioid dependence, the presence of a complex mechanism including the dopaminergic system, noradrenergic, serotonergic, etc. systems should be considered [51].

#### **1.5 Opioid withdrawal**

Withdrawal is a condition that occurs when the use of an exogenous substance that is used for a long time and develops physical dependence is interrupted. In opioid dependence, the mesocorticolimbic dopaminergic system activates and induces dopamine release in the NAc region. The adaptive increase in dopaminergic

### *Opium Alkaloids DOI: http://dx.doi.org/10.5772/intechopen.91326*

activity in CNS in opioid dependence is suppressed during withdrawal and withdrawal symptoms appear [52]. In addition to dopamine, different neurotransmitters and neuromodulators, such as noradrenaline, GABA, vasopressin, substance P, neuropeptide Y, and nitric oxide, are thought to play a role in the development of opioid withdrawal [53–55]. In opioid withdrawal syndrome, symptoms such as pain, insomnia, yawning, tremor, lacrimation, rhinorrhea, sweating, dehydration, goosebumps, mydriasis, restlessness, anorexia, nausea, vomiting, diarrhea, weight loss, hyperglycemia, hypotension, decrease in respiratory rate, hyperthermia and abdominal muscle cramps are seen [45].
