Since discovery by the Sumerians in 3300 BC, the opium poppy and its active ingredients, opiates such as morphine and codeine, have been recognized as powerful analgesic agents. Over the past two decades we have begun to understand many of the molecular mechanisms and neural circuits through which opiates exert their analgesic actions. In addition, we have come to realize that the neural networks involved in stimulation-produced and opiate-induced analgesia are intimately related.
Two key discoveries led to these advances. The first was the recognition that morphine and other opiates interact with specific receptors on neurons in the spinal cord and brain. The second was the isolation of endogenous neuropeptides with opiate-like activities at these receptors. The observation that the opiate antagonist naloxone blocks stimulation-produced analgesia provided the first clue that the brain contains endogenous opioids.
Endogenous Opioid Peptides and Their Receptors Are Distributed in Pain-Modulatory Systems
Opioid receptors fall into four major classes: mu (μ), delta (δ), kappa (κ), and orphanin FQ. The genes encoding each of these receptor types constitute a subfamily of G protein-coupled receptors. The μ receptors are particularly diverse; numerous μ receptor isoforms have been identified, many with different patterns of expression. This finding has prompted a search for analgesic drugs that target specific isoforms.
The opioid receptors were originally defined on the basis of the binding affinity of different agonist compounds. Morphine and other opioid alkaloids are potent agonists at μ receptors, and there is a tight correlation between the potency of an analgesic and its affinity of binding to μ receptors. Mice in which the gene for the μ receptor has been inactivated are insensitive to morphine and other opiate agonists. Many opiate antagonist drugs, such as naloxone, also bind to the μ receptor and compete with morphine for receptor occupancy without activating receptor signaling.
The μ receptors are highly concentrated in the superficial dorsal horn of the spinal cord, the ventral medulla, and the periaqueductal gray matter, important anatomical sites for the regulation of pain. Nevertheless, like other classes of opioid receptors, they are also found at many other sites in the central and peripheral nervous systems. Their widespread distribution explains why systemically administered morphine influences many physiological processes in addition to the perception of pain.
The discovery of opioid receptors and their expression by neurons in the central and peripheral nervous systems led to the definition of four major classes of endogenous opioid peptides, each interacting with a specific class of opioid receptors (Table 24–1).
Table 24–1Four Major Classes of Endogenous Opioid Peptides ||Download (.pdf) Table 24–1 Four Major Classes of Endogenous Opioid Peptides
|Propeptide ||Peptide(s) ||Preferential receptor |
|POMC || |
|Proenkephalin || |
|Prodynorphin || |
|Pro-orphanin FQ ||Orphanin FQ ||Orphan receptor |
Three classes—the enkephalins, β-endorphins, and dynorphins—are the best characterized. These peptides are formed from large polypeptide precursors by enzymatic cleavage (Figure 24–16) and encoded by distinct genes. Despite differences in amino acid sequence, each contains the sequence Tyr-Gly-Gly-Phe. There are two enkephalins, leucine and methionine enkephalin, which are closely related small peptides. β-endorphin is a cleavage product of a precursor that also generates the active peptide adrenocorticotropic hormone (ACTH). Both β-endorphin and ACTH are synthesized by cells in the pituitary and are released into the bloodstream in response to stress. Dynorphins are derived from the polyprotein product of the dynorphin gene. Enkephalins are active at both μ and δ receptors, whereas dynorphin is a relatively selective agonist of the κ receptor. The fourth endogenous opioid peptide is orphanin FQ or nociceptin (OFQ/N1–17). This 17-amino acid peptide is related in sequence to dynorphin and binds to the OFQ/N receptor.
Four families of endogenous opioid peptides arise from large precursor polyproteins.
A. Each of the precursor molecules is cleaved by proteolytic enzymes to generate shorter, biologically active peptides, some of which are shown in this diagram. The proenkephalin precursor protein contains multiple copies of methionine-enkephalin (M), leucine-enkephalin (L), and several extended enkephalins. Proopiomelanocortin (POMC) contains β-endorphin, melanocyte-stimulating hormone (MSH), adrenocorticotropic hormone (ACTH), and corticotropin-like intermediate-lobe peptide (CLIP). The prodynorphin precursor can produce dynorphin (D) and α-neoendorphin (N). The pro-orphanin precursor contains the orphanin FQ peptide (O). The black domains indicate a signal peptide.
B. Amino acid sequences of proteolytically processed bioactive peptides. The amino acid residues shown in bold type mediate interaction with opioid receptors. (Adapted, with permission, from Fields 1987.)
Members of the four classes of opioid peptides are distributed widely in the central nervous system and individual peptides are located at sites associated with the processing or modulation of nociceptive information. Neuronal cell bodies and axon terminals containing enkephalin and dynorphin are found in the dorsal horn of the spinal cord, particularly in laminae I and II, as well as in the rostral ventral medulla and the periaqueductal gray matter. Neurons that synthesize β-endorphin are confined primarily to the hypothalamus; their axons terminate in the periaqueductal gray region and on noradrenergic neurons in the brain stem. Orphanin FQ appears to participate in a broad range of other physiological functions.
Morphine Controls Pain by Activating Opioid Receptors
Microinjection of low doses of morphine or other opiates directly into specific regions of the rat brain produces a powerful analgesia. The periaqueductal gray region is among the most sensitive sites, but local administration of morphine into other regions, including the spinal cord, also elicits a powerful analgesia.
Morphine-induced analgesia can be blocked by injection of the opiate antagonist naloxone into the periaqueductal gray region or the nucleus raphe magnus (Figure 24–15). In addition, bilateral transection of the dorsal lateral funiculus in the spinal cord blocks analgesia induced by central administration of morphine. Thus the central analgesic actions of morphine involve the activation of descending pathways to the spinal cord.
In the spinal cord, as elsewhere, morphine acts by mimicking the actions of endogenous opioid peptides. The superficial dorsal horn of the spinal cord contains interneurons that express enkephalin and dynorphin, and the terminals of these neurons lie close to synapses formed by nociceptive sensory neurons and spinal projection neurons (Figure 24–17A). Moreover, the μ, δ, and κ receptors are located on the terminals of the nociceptive sensory neurons as well as on the dendrites of dorsal horn neurons that receive afferent nociceptive input, thus placing endogenous opioid peptides in a strategic position to regulate sensory afferent input. The number of μ receptors on Aδ nociceptors, which mediate fast and acute pain or "first pain", exceeds that on C fiber nociceptors, which mediate slow persistent pain or "second pain" (Figure 24–1). This may help to explain why morphine is more effective in the treatment of persistent rather than acute pains.
Local interneurons in the spinal cord integrate descending and afferent nociceptive pathways.
A. Nociceptive afferent fibers, local interneurons, and descending fibers interconnect in the dorsal horn of the spinal cord (see also Figure 24–3B). Nociceptive fibers terminate on second-order spinothalamic projection neurons. Local enkephalin-containing interneurons exert both pre- and postsynaptic inhibitory actions at these synapses. Serotonergic and noradrenergic neurons in the brain stem activate the local interneurons and also suppress the activity of the spinothalamic projection neurons.
B. Regulation of nociceptive signals at dorsal horn synapses. 1. Activation of a nociceptor leads to the release of glutamate and neuropeptides from the primary sensory neuron, producing an excitatory postsynaptic potential in the projection neuron. 2. Opiates decrease the duration of the postsynaptic potential, probably by reducing Ca2+ influx and thus decreasing the release of transmitter from the primary sensory terminals. In addition, opiates hyperpolarize the dorsal horn neurons by activating a K+ conductance and thus decrease the amplitude of the postsynaptic potential in the dorsal horn neuron.
Opiates regulate nociceptive transmission at synapses in the dorsal horn through two main mechanisms. First, they increase membrane K+ conductances in the dorsal horn neurons, hyperpolarizing the neurons and thus increasing the threshold for activation. Second, by binding to receptors on presynaptic sensory terminals opiates inhibit the release of neurotransmitter and thus decrease the extent of activation of the postsynaptic dorsal horn neurons. The decrease in neurotransmitter release appears to result from a decrease in Ca2+ conductance and consequent reduction of Ca2+ entry into the sensory nerve terminal (Figure 24–17B).
Many of the side effects of opiates are caused by the activation of opiate receptors within the brain and periphery. Opiate receptors are expressed by muscles of the bowel and anal sphincter; their activation contributes to constipation. The activation of opiate receptors in the nucleus of the solitary tract is responsible for respiratory depression and cardiovascular side effects. Confining drug administration to the spinal cord or to the periphery can minimize the side effects of systemic opiates. The release of endogenous opioid peptides from chromaffin cells of the adrenal medulla or from immune cells that migrate into injury sites may normally be involved in regulating the activation of nociceptors. The presence of peripheral opioid receptors has potential clinical relevance. Prolonged relief of pain after arthroscopic surgery can be achieved by injection of morphine into joints at doses that are ineffective when administered systemically. This peripheral route of opiate administration significantly reduces the side effects of opiate drugs.
Because the dorsal horn of the spinal cord has a high density of opioid receptors, morphine injected into the cerebrospinal fluid of the spinal cord subarachnoid space interacts with these receptors to elicit a profound and prolonged analgesia. Local administration of morphine is now commonly used in the treatment of postoperative pain, notably the pain associated with Caesarean section during childbirth. In addition to producing prolonged analgesia, intrathecal injection of morphine has fewer side effects because the drug does not diffuse far from its site of injection. Continuous local infusion of morphine to the spinal cord has also been used for the treatment of certain cancer pains.
Tolerance and Addiction to Opioids Are Distinct Phenomena
The chronic use of morphine invites major problems, most notably tolerance and addiction. The repeated use of morphine for pain relief can cause patients to develop resistance to the analgesic effects of the drug, with the consequence that progressively higher drug doses are required to achieve the same therapeutic effect.
What are the mechanisms underlying opiate tolerance? One theory holds that tolerance results from uncoupling of the opioid receptor from its G protein transducer. Nevertheless, the binding of naloxone to μ opiate receptors can precipitate withdrawal symptoms in tolerant subjects, suggesting that the opioid receptor is still active in the tolerant state. Tolerance may therefore also reflect a cellular response to the activation of opioid receptors, a response that counteracts the effects of the opiate and resets the system. Then, when the opiate is abruptly removed or naloxone is administered, this compensatory response is unmasked and withdrawal results.
Such physiological tolerance differs from addiction, a psychological craving for the drug. Psychological addiction almost never occurs when morphine is used to treat chronic pain.