MOR is the site of action of the endogenous peptides enkephalins, β(beta)-endorphin, dynorphin A, nociceptins, and agonists such as morphine, fentanyl congeners, methadone, and meperidine. The human MOR gene (OPRM1) spans over 200 kb and consists of 11 exons that combine to yield 17 splice variants [4, 5]. More than 700 single nucleotide polymorphisms have been described in the gene with variations that differ between races and ethnicities [5]. More clinically relevant is the fact that genetic variations in the OPRM1 gene can explain differences in the analgesic response to opioids between individuals [5, 6]. Thus, heterozygous patients with MOR A118G and G1947 mutations show less opioid consumption after surgery and homozygous carriers of both A118G and 158Met COMT allelic variants also require less morphine than their heterozygous counterparts [7–9].

MORs are located in the central nervous system (CNS) and in peripheral tissues of the body. Centrally, MORs are found in the periaqueductal gray (PAG) region of the brainstem and medial thalamus. MORs located at spinal level (superficial dorsal horn) also play a role in opioid-induced analgesia [10, 11]. Peripheral MORs have been found in leukocytes, myenteric cells, pulmonary neuroendoncrine and pancreatic cells, skeletal muscle, and nerve terminals located in the lung, joints, and blood vessels such as the portal vein [12].

The MOR belongs to the seven-transmembrane receptor superfamily. It is coupled with Gi/o proteins and as expected its activation is responsible for short- and long-term effects on neuronal and non-neuronal cells [13]. After binding of MOR agonists to the receptor, the release of the inhibitory G_i protein causes inhibition of adenylate cyclase, reduces cyclic 3 ′, 5 ′ adenosine monophosphate (cAMP), and reduces levels of protein kinase A activation [14]. MORs also modulate the activity of the G₀ protein, which inhibits Ca²⁺ and activates K⁺ channels [13]. The net result of activation of MORs is a decrease in the release of neurotransmitters (presynaptic) and hyperpolarization of membrane potentials (pre- and post-synaptic). MORs also have the ability to form dimers (homo or heterodimerization), which can also explain the differences in the analgesic response between subjects. In fact, the formation of heterodimers can alter agonist or antagonist selectivity, or switch intracellular signaling at the level of G proteins [15].

There are at least 2 well-described MOR subtypes receptors: mu1 (MOR1) and mu2 (MOR2). The analgesic effect of MOR agonists is caused by the binding to the MOR1 subtype receptor while their action on the MOR2 is responsible for most of the adverse effects related to opioids (respiratory depression, sedation, pruritus, prolactin release, dependence, anorexia, and sedation) [16, 17]. Interaction between the serotonergic and opioidergic systems also helps to explain the analgesic effects of opioids [18]. Acute morphine administration appears to enhance the synthesis, release, and metabolism of serotonin—especially in projection areas of the dorsal raphe nucleus and median raphe nucleus; in contrast, chronic exposure to morphine decreases release of 5-HT from the nerve terminals [18–20]. Furthermore, interaction with other receptors such as the dopaminergic (D1) receptors has been demonstrated in neurons of the cortex and caudate nucleus [21].

The orphan G protein-coupled receptor (GPCR) Opioid Receptor (NOP) is the most recently discovered opioid receptor [22]. Activation of the NOP receptor in supraspinal pain pathways (PAG) has hyperalgesic effects while its activation at the level of spinal structures appears to induce analgesia [23]. NOP receptors are insensitive to opioid agonists and antagonists such as morphine and naloxone. Noceptin/Orphanin FQ (N/OFQ) is the natural ligand peptide for the NOP receptor and does not show cross-reactivity with MORs. It is worth mentioning that the intrathecal administration of morphine and nociception has demonstrated supra-additive effects.

There are 4 chemical classes of opioids: phenanthrenes, benzomorphans, phenylpiperidines, and diphenylheptanes. Morphine, codeine, hydromorphone, levorphanol, oxycodone, hydrocodone, oxymorphone, buprenorphine, nalbuphine, and butorphanol belong to the phenanthrenes class. Pentazocine is a member of the benzomorphans class, and propoxyphene and methadone are classified in the diphenylheptanes class. Lastly, the phenylpiperidines include fentanyl, alfentanil, remifentanil, sufentanil, and meperidine. On the basis of their pharmacodynamics profiles, opioid analgesics can be classified as full agonists (i.e., morphine, fentanyl or remifentanil) or agonists-antagonists (i.e., buprenorphine, pentazocine and nalbuphine) [24]. Opioid agonists-antagonists can show high affinity for MOR but exhibit little efficacy [24].

Regardless of the route of administration, opioids need to cross the blood-brain barrier (BBB) in order to cause analgesia. The 2 main mechanisms of transport are passive diffusion and active transport, with the former being the most predominant method (◘ Table 7.2 [25–44]). Passive transport depends on the concentration of the drug, hydrophilicity, lipophilicity, and the degree of hydrogen bonding of the drug. It is generally accepted that hydrophilic opioids, such as morphine, will tend to accumulate in tissues with high contents of water and the opposite will occur with lipophilic drugs, such as fentanyl. Although passive diffusion of opioids across the BBB is accepted as the main kinetic mechanism of action, it cannot fully explain the kinetics of opioids in the CNS. For instance, the transport of morphine can be modulated by ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), whose expression appears to be decreased after long-term exposure to that opioid. Furthermore, the poor penetration of morphine has been linked to its active efflux from the brain to the blood by the P-gp at the BBB [45]. Therefore, passive and active mechanisms of transport govern the rate of diffusion of opioids across the BBB.

Morphine, one of the most commonly used opioids, is a full MOR agonist with poor liposolubility, low plasma protein binding (35%), and limited blood-brain barrier penetration [46, 47]. Hydromorphone, also a full agonist of MOR, is a semi-synthetic hydrogenated ketone derivative of morphine with a potency that is 7–10 times higher than its precursor [48]. Protein binding of hydromorphone is low (◘ Table 7.3) [49–55]. Fentanyl, a synthetic phenylpiperidine with high affinity for the MOR, is 80–100 times more potent than morphine; therefore, it is considered a strong opioid. Fentanyl has a high liposolubility, good penetration of the BBB, and is highly bound to proteins (84%) [56]. Alfentanil is an agonist of the MOR that has one-third to one-fourth of the potency of fentanyl. Alfentanil has a higher protein binding (79%) than fentanyl [56, 57]. Sufentanil is a thienyl analog of fentanyl with high liposolubility and a potency that is 3–5 and 5–10 times higher than fentanyl when given epidurally or intravenously, respectively [56]. Sufentanil is very highly protein bound (92.5%) [56]. Remifentanil is a 4-anilidopiperidine derivative of fentanyl and is an ultra-short-acting μ(mu)-opioid receptor agonist [58]. Meperidine is the least potent of the phenypiperidine class. In fact, it has approximately 10% of the effectiveness of morphine; however, some of its analgesic effects are related to its local anesthetic properties. Meperidine is not highly protein bound (58–75%) [59]. Methadone is a synthetic MOR agonist and an antagonist of the NMDA receptor. Methadone is formulated as a racemic mixture of 2 enantiomers; the R form binds to MOR, while S configuration acts as the NMDA antagonist. The S isomer also inhibits reuptake of serotonin and norepinephrine. Methadone is 60–90% bound to plasma proteins, mostly the acid α(alpha)1-globulins [60]. Tramadol is considered a weak MOR agonist. Tramadol has 1/10 of the potency of intravenous morphine [61]. It is formulated as a racemate, where the (+)-enantiomer stimulates MOR and inhibits reuptake of 5-HT, whereas the (−)-enantiomer inhibits noradrenaline reuptake [62]. Tramadol is 20% plasma protein bound [63]. Propoxyphene is a weak synthetic analgesic with a similar structure to methadone and an equipotency similar to codeine. Some of the analgesic effects of propoxyphene can be explained by its antagonistic actions on the NMDA receptor; however, its use has been discouraged because of significant adverse effects [64]. Tapentadol is a novel MOR agonist and inhibitor of norepinephrine uptake. Tapentadol is 2–3 times less potent than morphine and has shown low protein binding. Cebranopadol is a newly developed nociceptin receptor (NOP) agonist that has also cross-reactivity with MORs, δ(delata), and κ(kappa) receptors. In rodents, cebranopadol is 180–4800 times more potent than morphine and has shown analgesic actions in inflammatory, neuropathic, and bone cancer pain [65, 66]. Cebranopadol is not available for clinical use in humans.