The Opiates – Opioids and Pain
Although we all feel that we intuitively understand what pain is like, it is really far more complex than generally believed. Since opioids are therapeutically best known as analgesics, a further discussion of pain and its neural circuitry is needed.
Pain is distinct from other sensory systems in that it can be caused by a variety of stimuli detected by several types of nociceptors (detectors of noxious stimuli). The nociceptors are networks of free nerve endings that are sensitive to intense pressure, extreme temperature including heat and cold, electrical impulses, cuts, chemical irritants, and inflammation. Pain varies not only in intensity but also in quality and may be described as “pricking,” “stabbing,” “burning,” “aching,” and so forth. Its perception is also highly subjective, and no single stimulus will be described as painful by all individuals nor perhaps even by the same individual under different circumstances. Pain is modified by a number of factors including strong emotion, environmental stimuli like stress, hypnosis, acupuncture, and opiate drugs.
Although we can get subjective reports of pain, quantification is difficult, particularly when testing analgesic drugs. In the laboratory, when methods such as the application of sudden pressure, pinpricks, or stabs are used to induce pain, most analgesic drugs show ineffective or inconsistent analgesic effects. The failure of these drugs to show a significant reduction in pain is probably because of the low emotional impact of those types of pain. More consistent results are obtained with the analgesics through the use of techniques that produce slowly developing or sustained pain. One technique used with human subjects is to stop blood flow to an exercising muscle with a tourniquet. With this method, the pain is slow in onset and is directly related to amount of exercise. Cutaneous pain in humans can be produced by the intradermal injection of various chemicals.
A reliable method to test this kind of pain uses canthardin to induce a blister, from which the outer layer of epidermis is removed to expose the blister base, on which small quantities of various agents can be applied for testing. Techniques that have been designed to produce moreintense or morepersistent pain are infrequently used because finding subjects willing to participate in such experiments is more difficult. Animal testing is overall more reliable, yielding conditions that are comparable to pathological pain in humans. This may be because the human subject in the experimental setting realizes that the pain stimulus poses no real threat, whereas for the animal subject, all pain is potentially serious. Animal tests are described in an earlier post.
The two components of pain have distinct features
Pain is often described as having several components. “First,” or early, pain represents the immediate sensory component and signals the onset of a noxious stimulus and its precise location to cause immediate withdrawal and escape from the damaging stimulus. “Second,” or late, pain has a strong emotional component, that is, the unpleasantness of the sensation. Adaptation occurs more slowly to the secondary component, so it attracts our attention in prolonged fashion to motivate behaviors that limit further damage and aid recovery. Late pain is less localized and is often accompanied by autonomic responses such as sweating, fall in blood pressure, or nausea.
These distinct components of pain are in part explained by the types of neuron that carry the signal. Fibers called A5 are larger in diameter and are myelinated, so they conduct action potentials more rapidly than the thin and unmyelinated C fibers. The difference in speed explains why when you smash your finger in the car door, you first experience a sharp pain that is well localized but brief, followed by a dull aching that is a prolonged reminder of the damage your body has experienced. These neurons have their cell bodies in the dorsal root ganglia and terminate in the gray matter of the dorsal horn of the spinal cord, ending on projection neurons that transmit pain signals to higher brain centers.
A second distinction between the two components of pain is their route and final destination in the brain. Early pain is transmitted from the spinal cord via the spinothalamic tract to the posteroventrolateral nucleus of the thalamus before going directly to the primary and then secondary somatosensory cortex. The primary somatosensory cortex provides sensory discrimination of pain, while the secondary cortex is involved in the recognition of pain and memory of past pain. Late pain also goes to the thalamus, but in addition gives off collaterals to a variety of limbic structures such as the hypothalamus and amygdala as well as the anterior cingulate cortex. The anterior cingulate has a role in pain affect, attention, and motor responses (Rainville, 2002).
For the first time, researchers have been able to demonstrate the temporal relationship between painevoked cortical activation and reported pain in human subjects. Ploner and colleagues (2002) subjected individuals to brief painful laser stimuli and continuously monitored the subjects’ subjective pain rating while simultaneously recording faint magnetic fields on the surface of the skull using magnetoencephalogra phy (MEG). Although MEG is somewhat inaccurate in precisely locating brain activity, it is excellent at showing the neural changes over very small units of time (from one millisecond to another). In that way Ploner could trace a wave of brain activity from its origin to sequential brain areas during processing. When the cortical activation was superimposed on magnetic resonance images, they showed that first pain (pain recogntion), identified by subjects’ ratings, was temporally related to activation of the primary somatosensory cortex, whereas second pain (identified by subjects’ ratings of unpleasantness) was strongly associated with anterior cingulate activation. Both types of pain were associated with neural activity in the secondary somatosensory cortex.
Opioids inhibit pain transmission at spinal and supraspinal levels
By binding to opioid receptors, morphine and other opiate drugs mimic the inhibitory action of the endogenous opioids at many stages of pain transmission within the spinal cord and brain. To simplify, we can say that opiates regulate pain in three ways:
1. Within the spinal cord by small inhibitory interneurons;
2. By two significant descending pathways originating in the periaqueductal gray (PAG); and
3. At many higher brain sites, which explains opioid effects on emotional and hormonal aspects of pain response.
As you know, information about pain, either from the surface or deep within the body cavity, is carried by neurons from the body into the spinal cord. Some of these primary afferent neurons end directly on projection neurons that transmit pain signals to higher brain centers (e.g., first to the thalamus and then to the somatosensory cortex). Others end on small excitatory interneurons (i.e., short neurons within the spinal cord) that in turn synapse onto the projection neurons.
Opioids reduce the transmission of pain signals at the spinal cord in two ways. First, small inhibitory spinal interneurons release endorphins that inhibit the activation of the spinal projection neurons. Morphine can act directly on those same opiate receptors to inhibit the transmission of the pain signal to higher brain centers that normally allow us to become aware of the sensory experience. Second, endorphins regulate several modulatory pathways that descend from the brain to inhibit spinal cord pain transmission either by directly inhibiting the projection neuron (A), or the excitatory interneuron (B), or exciting the inhibitory opioid neuron (C). These descending modulatory pathways begin in the midbrain and modify the pain information carried by spinal cord neurons.
The most important descending pathways begin in the PAG. The PAG is a brain area rich in endogenous opioid peptides and high concentrations of opioid receptors, particularly (I and K. Local electrical stimulation of the PAG produces analgesia but no change in the ability to detect temperature, touch, or pressure. Treatment of chronic pain in human patients with electrical stimulation of the PAG is frequently successful, although tolerance occurs with repeated use and crosstolerance with injected morphine also occurs. This phenomenon suggests that electrical stimulation releases a morphinelike substance onto the same postsynaptic receptor sites occupied by exogenous morphine. Partial blockade of stimulationinduced analgesia with the specific opioid antagonist naloxone further supports that idea.
The neurons beginning in the PAG end on cells in the medulla, including the serotonergic cell bodies of the nucleus of the raphe nuclei. Microinjection of opioids into the raphe produces significant analgesia. The serotonergic neurons descend into the spinal cord to inhibit cell firing there and in that way reduce pain transmission.
Other cells originating in the PAG terminate in the brain stem in an area close to the locus coeruleus, an important cluster of noradrenergic cell bodies that also send axons to the spinal cord. Locus coeruleus cells increase their firing rate when noxious stimuli are applied. The same cells are hyperpolarized by |ireceptor agonists, which reduces their firing rate. Furthermore, neurotoxic lesions of the descending serotonergic and noradrenergic cells prevent systemic morphine induced analgesia. Therefore, there are at least two major pathways that descend to the spinal cord to inhibit the pro jection of pain information to higher brain centers. However, the inhibitory action is direct in some cases, while at other times the inhibition occurs by acting on small spinal interneurons.
In summary, opioids modulate pain directly in the spinal cord and also by regulating the descending pain inhibitory pathways ending in the spinal cord. In addition, significant opioid action also occurs in other supraspinal (above the spinal cord) locations, including higher sensory areas and limbic structures as well as the hypothalamus and medial thalamus. A high concentration of endogenous opioids and the pres ence of opiate receptors suggest that these areas may be responsible for the emotional component of pain as well as autonomic and neuroendocrine respons es. In a recent PET study, the endogenous activation of the |iopioid system was evaluated during sustained pain. Zubieta and colleagues (2001) found a significant negative correlation between (iopioid activity (measured as displacement of [uC]carfentanil from (ireceptors) in the nucleus accumbens, amygdala, and thalamus and reported sensory pain scores. That is, the greater the |iopioid activation, the lower was the individual’s sen sory pain score. The PAG also showed increased (ireceptor displacement, although it was not signifi cant. When the scores on the affective component of pain were evaluated, increased Uopioid activity was found in the bilateral anterior cingulate cortex, thalamus, and nucleus accumbens. These results indicate that endogenous |Jopioids modulate both the sensory and emotional components of pain and that morphine and other opiates likewise act at these sites. The existence of multiple circuits carrying pain information demonstrates the redundancy and diffuse nature of pain trans mission, which reflects its tremendous evolutionary significance for survival.