The Opioids

Narcotic Analgesics

Opioid Receptors and Endogenous Neuropeptides

• Opiates are natural narcotics derived from the opium poppy. Other narcotics are semisynthetic or totally synthetic.
• Minor differences in molecular structure determine whether the drugs are full agonists, partial agonists, or pure antagonists.
• Opioids relieve pain and produce drowsiness and sleep. Euphoria or dysphoria may occur. Opioids cause pinpoint pupils, vomiting, suppression of the cough reflex, drop in body temperature, reduced appetite, constipation, and a variety of hormonal effects. Respiratory and cardiac depression may also occur at higher doses.
• Repeated use produces tolerance to many but not all of the drugs’ effects, as well as physical dependence.
• There are four opioid receptors (μ, δ, κ, and NOP-R), which are widely and unevenly distributed in the central and peripheral nervous systems. Opioids and opioid neuropeptides bind to the three classical receptors but not to NOP-R. Nociceptin/orphanin FQ is the neuropeptide that binds to NOP-R but not to the three classical receptors. Each of the receptors has been isolated and cloned and examined with membrane protein crystallization to visualize in ultra-high resolution their three-dimensional structures. All four are coupled to G proteins that induce metabotropic effects. The principal cellular activities include actions on ion channels (open K⁺, close Ca²⁺), which are responsible for cell hyperpolarization and inhibition of neurotransmitter release, and inhibition of adenylyl cyclase.
• Endogenous ligands for the opioid receptors are small peptides that are cleaved from larger propeptides manufactured in the soma. Molecular biology has shown four distinct propeptides (prodynorphin, POMC, proenkephalin, and pronociceptin/orphanin FQ), which produce a variety of opioid and non-opioid fragments. The propeptide for a fifth endogenous peptide endomorphin is not known.
• Endogenous opioids inhibit synaptic transmission by postsynaptic inhibition, by axoaxonic inhibition, and via presynaptic autoreceptors.
• The locations of these peptides in the brain, spinal cord, and pituitary implicate them in regulating pain, reward, stress response, water balance, feeding, body temperature, and endocrine function. Nociceptin/orphanin FQ acts at cellular and molecular levels much the same way as opioids but often produces different and opposing effects. See Table 11.1 for locations, functions, and endogenous ligands for opioid receptor subtypes.

Opioids and Pain

• Nociceptors are free nerve endings that are sensitive to a variety of pain stimuli.
• Pain has two components. First pain is the immediate sensory component carried by myelinated Aδ neurons and transmitted via the spinothalamic tract to the PVL nucleus of the thalamus before projecting to primary, then secondary, somatosensory cortex. Second pain is the emotional component carried by C fibers and transmitted to the thalamus with collaterals to limbic areas, including the anterior cingulate.
• Opioids (both endogenous and exogenous) act at spinal and supraspinal levels to relieve pain. Endorphin neurons in the spinal cord decrease the conduction of pain signals from the spinal cord to higher brain centers. Descending neurons from the periaqueductal gray activate pathways from the locus coeruleus (noradrenergic) and nucleus of the raphe (serotonergic) that impede pain signals in the spinal cord. Opioid receptors in the neocortex and limbic regions modulate the emotional component of pain to relieve the sense of suffering.
• Analgesic effects of electroacupuncture depend on opioids. Acupuncture induced by 100 Hz is blocked by κ-receptor antagonists, shows cross-tolerance to κ-agonists, and increases CSF levels of dynorphin. Acupuncture induced by 2 Hz is antagonized by δ-receptor blockers, shows cross-tolerance to δ-agonists, and elevates proenkephalin.
• Analgesia can be produced by drugs that inhibit both of the enkephalin degrading enzymes. Elevating endogenous enkephalin has fewer side effects than morphine: less respiratory depression, partial tolerance, and low abuse potential.
• A gene therapy clinical trial showed that the gene coding for proenkephalin carried by a herpes simplex viral vector reduced pain in patients with cancer with minimal side effects.
• Dual μ-receptor/NOP-R agonists produce analgesia without respiratory depression, cardiovascular effects, physical dependence, or abuse liability.

Opioid Reinforcement, Tolerance, and Dependence

Treatment Programs for Opioid Use Disorder

• Predicting which patients receiving opioids for pain will become chronic drug users is difficult. Physicians struggle with the dilemma of needing to treat serious pain and yet follow new CDC guidelines that want to limit opioid prescriptions because of the rising number of opioid fatalities.
• Animal studies show that opioids have reinforcing effects in self-administration paradigms, in conditioned place preference, and in reducing the threshold for electrical self-stimulation of the brain.
• Opioid drugs inhibit inhibitory GABA cells, increasing mesolimbic cell firing and DA release in the NAcc. Both dopaminergic and nondopaminergic mechanisms are necessary for the reinforcing effects.
• Opioid drugs demonstrate tolerance to many of the drug effects and cross-tolerance with other drugs in the same class, as well as with endogenous opioids.
• Prolonged use produces physical dependence, which is characterized by a classic rebound withdrawal syndrome that includes many flu-like symptoms, insomnia, depression, and irritability. Cross dependence means that any drug in the opioid family can abruptly stop withdrawal symptoms.
• A model of the physiological mechanism for tolerance and dependence is the compensatory response of cells in the locus coeruleus to the acute inhibition of adenylyl cyclase. Tolerance may also be due to uncoupling of the receptor from G protein, down-regulation of receptors, or receptor internalization.
• Classical conditioning of environmental cues associated with components of drug use is important in the development of tolerance and in maintaining the drug habit. Conditioned craving is significant in producing relapse in the detoxified addict.
• Detoxification is the first step in drug abuse treatment.
• Opioid abuse treatment programs include the substitution of another opioid, such as methadone or buprenorphine, for the abused drug. These substitutes, when given orally, produce no euphoria but eliminate craving for heroin and reduce exposure to HIV and hepatitis. The long-acting opioids stabilize the physiological effects and encourage contact with support staff. Methadone has a mild withdrawal. There are few damaging effects on organs with prolonged use.
• Compared with methadone, buprenorphine is longer acting, has a milder withdrawal and neonatal withdrawal, and can be prescribed in a physician’s office. When combined with naloxone, abuse potential is reduced. An implantable device to administer buprenorphine has multiple advantages over the pill form of the drug.
• Maintenance treatment with methadone or buprenorphine is preferable to heroin use in pregnant addicts. Buprenorphine and methadone are equally effective in reducing heroin use but buprenorphine may have advantages in fetal outcome.
• Opioid antagonists are effective in blocking the opioid receptors so that self-administered narcotics have no effect.
• In rats, heroin vaccine binds to drug molecules, which prevents entry to the CNS and reduces self-administration of opioids.
• The most successful treatment approaches are multidimensional ones.