Opioid Receptor Ligands and Sites of Action

16 May

Endogenous Ligands Pentapeptides  that mimic opioid activity and activate opioid receptors were initially  isolated  from  brain  extracts.  Two isoforms  were identified:  Met- enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) (Hughes et al. 1975). The same and other opioid peptides (endorphins, END; dynorphins, DYN) were later isolated from brain, spinal cord, pituitary gland, adrenals, immune cells, and other tissues. The amino-terminal of these opi- oid peptides  contains  the Tyr-Gly-Gly-Phe-[Met/Leu] sequence. Three dis- tinct opioid precursors  have been identified  so far: prodynorphin (PDYN), proopiomelanocortin (POMC), and proenkephalin (PENK) (Comb et al. 1982; Kakidani et al. 1982; Nakanishi  et al. 1979). Each of these precursors  un- dergoes processing  by proteolytic  enzymes into  DYN, END, and  ENK, re- spectively. The POMC gene is transcribed  and translated  into a prohormone of 267 amino acids. Posttranslational processing of this large precursor  pep-tide produces several smaller peptides, including β-endorphin, α-melanocyte- stimulating  hormone  (α-MSH), and ACTH. Posttranslational processing of PENK results  in Met-enkephalin,  Leu-enkephalin,  and  a number  of other enkephalins,  including bovine adrenal medulla peptide 22. The PDYN gene produces a prohormone of 254 amino acids, which encodes the opioid pep- tides dynorphin  A and B (Höllt 1993). END, ENK, and DYN can bind to any of the known opioid receptors  with varying affinities. In addition,  a novel family of endogenous opioid peptides have been discovered and termed en- domorphins (Zadina  et  al. 1997). Endomorphin-1   (Tyr-Pro-Trp-Phe)  and endomorphin-2 (Tyr-Pro-Phe-Phe)  bind to the μ-receptor with high affinity (Horvath 2000).

Endogenous opioid peptides can be released from neurons and axon termi- nals by depolarization and can exert pre- and postsynaptic effects. In addition, endogenous opioids are produced in many nonneuronal tissues, notably also in lymphocytes, monocytes, and granulocytes in inflamed tissue (Rittner et al.

2001). In models of inflammatory  pain, opioid peptide-containing immune cells migrate from the circulation to the injured tissue. Selectins and integrins

have been identified as important adhesion molecules which regulate the mi- gration of opioid-containing immune cells (Machelska et al. 1998, 2002). Upon

exogenous stressful stimuli or releasing agents (e.g., cold water swim stress, postoperative pain, corticotropin releasing factor, catecholamines), these pep- tides can be locally released and subsequently bind to opioid receptors on sen- sory neurons. By inhibiting the excitability of these neurons, they can increase

nociceptive thresholds  (i.e., produce analgesia; Stein et al. 1993). Preclinical research  using protease  (“enkephalinase”)  inhibitors  to increase concentra-

tions of endogenous opioid peptides in various central and peripheral tissues is ongoing but has not resulted in clinical applications for pain treatment  so far (Roques 2000).

Exogenous Ligands

Exogenous opioid ligands can be classified into three groups: full agonists, partial agonists/antagonists, and full antagonists.  The standard  to which all other opioid analgesics are compared is morphine. Although the alkaloid mor- phine was isolated in the early 1800s the structure of morphine was identified only in 1925 by Gullard and  Robinson  (Fig. 3a). It was hypothesized  that the piperidine  ring is essential for its pharmacological  activity. The nitro- gen atom of this ring is normally positively charged and can interact  with

Fig. 3a–d Structures of classical opioid receptor agonists: a morphine, b the 4- phenylpiperidine  fentanyl, and c the diphenylpropylamine methadone. d Structure of the classical opioid receptor antagonist naloxone

a negatively charged counterpart. Many pharmacologists  and chemists tried to produce more potent synthetic opioids with less physical and psychological dependence.  The 4-phenylpiperidines  (e.g., fentanyl; Fig. 3b), the diphenyl- propylamines (e.g., methadone; Fig. 3c), and many derivatives (e.g., alfentanil, sufentanil,  remifentanil)  have different  structures  from morphine.  Ligands at μ-receptors produce potent analgesia; however, they also produce side ef- fects like respiratory  depression, constipation,  physical dependence, and tol- erance. In 1942 the substitution  of an allyl group for the methyl group on the nitrogen  atom  of morphine  produced  the first opioid receptor  antago- nist, nalorphine.  Nalorphine not only countered  the effects of morphine  but

also produced limited analgesia mediated through κ-opioid receptors. An ad- ditional  member  of this mixed agonist/antagonist group is buprenorphine, a semi-synthetic opiate derivative of thebaine. Buprenorphine  is a partial ag-

onist at the μ-receptor.  At low doses it produces  typical morphine-like  ef- fects, and  at higher  doses it has a reduced  intrinsic  activity compared  to pure  agonists  (Cowan et al. 1977). Buprenorphine  also has the properties

of a κ-receptor  antagonist  (Negus et al. 1989). Naloxone was developed as a pure opioid receptor  antagonist,  which has a structure  similar to that  of morphine  (Fig. 3d). Several newer compounds  with restricted  access to the CNS have been synthesized. These were designed with the aim to activate pe-

ripheral opioid receptors exclusively, without the occurrence of central side effects (Binder et al. 2001; Furst et al. 2005; Kumar  et al. 2005; Whiteside et al. 2004).

Sites of Action

Supraspinal and Spinal Sites

Various major brain regions containing opioid peptides and opioid receptors have been identified including the periaqueductal  gray, the locus coeruleus, and the rostral  ventral medulla (Heinricher  and Morgan 1999; Fig. 4a). All three opioid receptors are also present in the dorsal horn of the spinal cord, which is in another  area important for opioid-induced  analgesia (Fig. 4b).

The μ-, δ-, and κ-opioid receptors are mainly located in the upper laminae, particularly the substantia gelatinosa (laminae I and II). In addition, δ-opioid

receptors are found in the deeper laminae of the dorsal horn and in the ven- tral horn (Gouarderes et al. 1993). Opioid receptor activation mostly results in depression  of neuronal  firing. Presynaptically, opioids inhibit Ca2+ influx and the subsequent release of glutamate and neuropeptides (e.g., substance P,

calcitonin gene-related peptide) from primary afferent terminals. Postsynap- tically, opioids hyperpolarize ascending projection neurons by increasing K+ conductance.

Fig. 4a An autoradiographic receptor  binding  technique  showing the distribution  of μ- receptors within rat brain slices. An increase in μ-receptor density (indicated with arrows) shows their distribution  in various regions, including the cortex, thalamus, hypothalamus, and brainstem.  b Immunocytochemical studies showing μ-receptors  within laminae I–II of spinal cord dorsal horns from rats (kindly provided by Dr. S. Mousa). c Immunocyto- chemical studies from rat hindpaw preparations indicating μ-receptors on primary afferent neurons (also kindly provided by Dr. S. Mousa)

Peripheral Sites

It became clear in the late 1980s that opioid receptors  and opioid peptides are also located in the peripheral nervous system, including primary afferent neurons  and dorsal root ganglia (DRG) (Stein et al. 1989; Stein et al. 2003). Opioid receptors have been shown mainly on small- to medium-diameter neu- ronal cell bodies of sensory neurons  (Mousa et al. 2000). After synthesis in the DRG, opioid receptors are transported to the peripheral nerve terminals of primary afferent neurons (Hassan et al. 1993; Fig. 4c). Opioid receptors are also expressed by neuroendocrine (pituitary,  adrenals),  immune,  and ecto- dermal tissues (Slominski et al. 2000). Although opioids increase potassium currents  in the CNS it is still controversial whether this occurs in DRG neu-

rons. Rather, it was shown that the modulation of Ca2+ currents is the principal mechanism for the inhibitory effect of opioids on sensory neurons (Akins and

McCleskey 1993). Recently, G protein-coupled inwardly rectifying potassium channels (GIRK2) and μ-opioid receptors were colocalized on sensory nerve endings in epidermis, and it was proposed that endothelin-B receptors trigger the release of endorphin  from keratinocytes, suppressing pain via opioid re- ceptors coupled to GIRK channels (Khodorova et al. 2003). In addition, it was shown that opioids activate inhibitory Gi/o proteins, which leads to a decrease of cAMP in peripheral sensory neurons (Chen et al. 1997).

Peripheral Opioid Receptors and Inflammation

In animal experiments,  local application  of opioid receptor  agonists elicits a more pronounced antinociceptive effect under painful inflammatory condi- tions than in noninflamed  tissue. It was shown that subcutaneous  inflamma- tion can induce an upregulation of μ-opioid receptor mRNA within the lumbar spinal cord (Maekawa et al. 1996) and DRG (Puehler et al. 2004). In addition, the expression of opioid receptors in sensory neurons increases time-dependently during inflammation (Zöllner et al. 2003). Subsequently, the axonal transport of opioid receptors to the peripheral nerve terminals is augmented (Hassan et al.

1993; Laduron and Castel 1990). This increase might be related to cytokines

(e.g., interleukin 4) through the binding of STAT-6 transcription factors to the μ-opioid receptor gene promoter  (Kraus et al. 2001). Other potential mecha- nisms contributing  to enhanced antinociceptive  efficacy include an increase in the number of opioid receptor bearing peripheral sensory nerve terminals (Stein et al. 2003), an increase in G protein  coupling (Shaqura  et al. 2004; Zöllner et al. 2003), a disruption  of the perineural  barrier (Antonijevic et al.

1995), and an enhanced opioid receptor trafficking to the neuronal membrane

(Patwardhan et al. 2005).

Clinical Applications

Acute Pain

Opioids are the most broadly effective analgesics and are used in both acute and chronic pain. Typical acute pain situations include intraoperative,  post- operative, and posttraumatic pain. In those situations  opioids are used pre- emptively (i.e., before occurrence  of an anticipated  noxious  stimulus,  e.g., during  induction  of anesthesia)  or therapeutically  (i.e., after occurrence  of noxious stimulation). Whereas acute pain is generally amenable to drug ther- apy, chronic pain is a complex disease in its own right and needs to be differ- entiated into malignant (cancer-related) and nonmalignant (e.g., neuropathic,

inflammatory)  pain. Acute and cancer-related pain are commonly responsive to opioids. Chronic nonmalignant pain requires a multidisciplinary approach encompassing  various pharmacological  and nonpharmacological  (e.g., psy- chological, physiotherapeutic) treatment  strategies. Various routes of opioid administration (e.g., oral, intravenous,  subcutaneous,  intrathecal,  epidural, topical, intraarticular, transnasal) are used, depending on the clinical circum- stances. The opioid effect is a selective one on nociception. Touch, pressure, and other sensory modalities are generally unaffected. After systemic adminis- tration, forebrain mechanisms play a prominent role in the clinical effects, and a common clinical manifestation of opioid analgesia is a change in the affective response to pain. Spinal mechanisms become proportionally  more important when opioids are given by neuraxial injection. Patients given systemic opioids will typically say that pain is still present, but the intensity is reduced and it no longer bothers them as much. Mental clouding and dissociation from pain is often accompanied by mood elevation.

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