Opioid Receptors

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Chapter: Essential pharmacology : Opioid Analgesics And Antagonists

Morphine and other opioids exert their actions by interacting with specific receptors present on neurones in the CNS and in peripheral tissues.



Morphine and other opioids exert their actions by interacting with specific receptors present on neurones in the CNS and in peripheral tissues. Chemical modification of morphine structure has yielded a number of compounds which have a complex pattern of morphinelike and other agonistic and antagonistic actions that cannot be explained on the basis of a single opioid receptor. Radioligand binding studies have divided the opioid receptors into three types (μ, κ, δ); which have been cloned. Each has a specific pharmacological profile and pattern of anatomical distribution in the brain, spinal cord and peripheral tissues. Subtypes of μ and κ receptor have been identified. The proposed functional role of the 3 types of opioid receptors is listed in Table 34.1.


Opioid ligands can interact with different opioid receptors as agonists, partial agonists or competitive antagonists. The overall pattern of effect of a particular agent depends not only on the nature of its interaction with different opioid receptors, but also on its relative affinity for these, e.g. morphine is an agonist on μ, κ and δ receptors, but its affinity for μ receptors is much higher than that for the other two. The effects, therefore, are primarily the result of μ receptor activation.


The nature and intensity of action of complex action opioids and antagonists are summarized in Table 34.2.


μ receptor


The μ receptor is characterized by its high affinity for morphine. It is the major receptor mediating actions of morphine and its congeners. Endogenous ligands for μ receptor— peptides called Endomorphins 1 and 2—have only recently been found in mammalian brain—produce biological effects ascribed to this receptor. Other opioid peptides viz. βendorphin, enkephalins and dynorphins bind to μ receptor with lower affinity. βfunaltrexamine is a relatively selective but irreversible μ antagonist. High density of μ receptors has been detected in periaqueductal gray, thalamus, nucleus tractus solitarious, nucleus ambiguus and area postrema.


Two subtypes of μ receptor have been proposed:


μ1: Has higher affinity for morphine, mediates supraspinal analgesia and is selectively blocked by naloxonazine.


μ2: Has lower affinity for morphine, mediates spinal analgesia, respiratory depression and constipating action.

κ receptor


This receptor is defined by its high affinity for ketocyclazocine and dynorphin A; the latter is considered to be its endogenous ligand. Norbinaltorphimine is a selective κ antagonist. Two subtypes of κ receptor κ1 and κ3 are functionally important. Analgesia caused by κ agonists is primarily spinal (through κ1 receptor). However, κ3 receptors mediate lower ceiling supraspinal analgesia. Other κ actions are listed in Table 34.1.


δ receptor


This receptor has high affinity for leu/met enkephalins which are its endogenous ligands. The δ mediated analgesia is again mainly spinal (δ receptors are present in dorsal horn of spinal cord), but the affective component of supraspinal analgesia appears to involve δ receptors because these receptors are present in limbic areas—also responsible for dependence and reinforcing actions. The proconvulsant action is more prominent in δ agonists. Myenteric plexus neurones express high density of δ receptors—mediate reduced g.i. motility. Naltrindole is a selective δ antagonist.


It thus appears that μ and δ receptor responses are quite similar, but those exerted through κ receptor are distinct. In certain areas κ actions are antagonistic to μ actions.


The σ (sigma) receptor is no longer considered an opioid receptor, because it is neither activated by morphine nor blocked by naloxone. However, certain opioids, e.g. pentazocine, butorphanol and many unrelated compounds (including some hallucinogens) bind to σ receptors. Certain naloxone insensitive effects of pentazocine like drugs, e.g. dysphoria, psychotomimetic action, tachycardia, mydriasis are believed to be mediated by σ receptors.


Opioid Receptor Transducer Mechanisms


All 3 types of opioid receptors (μ, κ, δ) have been cloned; all are Gprotein coupled receptors located mostly on prejunctional neurones. They generally exercise inhibitory modulation by decreasing release of the junctional transmitter (Fig. 34.1). As such, various monoaminergic (NA, DA, 5HT), GABA, glutamate (NMDA/ AMPA) pathways are intricately involved in opioid actions.



Opioid receptor activation reduces intracellular cAMP formation and opens K+ channels (mainly through μ and δ receptors) or suppresses voltage gated N type Ca2+ channels (mainly κ receptor). These actions result in neuronal hyperpolarization and reduced availability of intracellular Ca2+ decreased neurotransmitter release by CNS and myenteric neurones (e.g. glutamate from primary nociceptive afferents).

However, other mechanisms and second messengers may also be involved, particularly in the long-term.


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