The sensation of pain represents a complex series of events designed to protect the central nervous system (CNS). The integration of multiple components of the neuroaxis begins with activation of specific nociceptors, signaling potential injury to sensory fibers and potential damage to the CNS. This type of neuropathic pain is considered maladaptive, yielding harmful sequelae. Nocice-ptive pain is, however, more of a warning to the rest of the body, indicating some form of injury, signifying that further investigation and action is warranted (5). Nociceptors are not specialized pain receptors, but rather they are simply bare nerve endings in the periphery. In 1965, Melzack and Wall first described the gate control theory of pain, which integrates the anatomic pain pathways and several psychological pain models (6). The gate control theory of pain proposes a neural mechanism in the dorsal horn of the spinal cord that acts like a gate, blocking or allowing the transmission of pain impulses from the periphery to the brain. The smaller unmyelinated fibers transmit impulses slowly and result in dull pain such as burning and aching. The large myelinated fibers transmit impulses quickly and are associated with acute, sharp types of pain. The large fibers typically produce the acute initial pain sensation, but small fiber stimulation can produce chronic pain that worsens with time. The magnitude of the response is proportional to the intensity of the stimulus and thus proportional to the magnitude of the injury. In addition, the two types of impulses can be antagonistic. For example, mild stimulation of the large fibers can greatly diminish the pain produced by the stimulation of small fibers, which is the gating mechanism used to explain the effectiveness of topical counterirritants as well as electrical and physical pain treatment modalities. The autonomic nervous system is integrally related in the pain experience as the afferent sympathetic chain ganglia fibers connect with the same spinal cord cells that receive input from the peripheral nociceptive fibers. Although the normal dorsal root ganglion demonstrates minimal sympathetic innervation, it demonstrates a marked enhancement in the levels of sympathetic innervation following peripheral injury.
Although the first intrathecal injection of morphine was reported in 1901, it was not until the 1960s and 1970s that the effects of opioids on the CNS were studied extensively (7). The first proposal of a descending system of pain modulation was proposed in 1906 by Sherrington (8). The description of stereospecific opioid receptors was first made in the early 1970s, helping to characterize further the suggestion that the analgesic effects of opioids involve a descending inhibitory system originating in the brain stem and affecting dorsal horn nociceptive transmission (9). Just half a decade after the discovery of specific opioid receptors, it was shown that opioids exert their effects by binding selectively to and altering the conformation of stereospecific opioid receptors (10).
In the periaqueductal gray, substance P neurons from the ascending nociceptive system stimulate cells that contain the opioid enkephalin. These enkephalin-containing cells then inhibit interneurons, which are also inhibited by P-endorphin-containing cells in the hypothalamus (11). These interneurons inhibit the main outflow neuron of the periaqueductal gray to the rostral ventral medulla. The inhibitory interneurons then result in increased transmission from the outflow neurons in the periaqueductal gray to the rostral ventral medulla (12). The input from the periaqueductal gray then stimulates an output cell in the rostral ventral medulla, which may contain norepineph-rine, enkephalin, and substance P as its neurotransmitters. The norepinephrine-containing neurons inhibit the main outflow neuron, but neurons containing a local opioid, such as enkephalin or dynorphin, can inhibit the norepi-nephrine neuron. The outflow neurons appear to be inhibitory via receptors on thalamic-projecting neurons. These nociceptor neurons are targets of the spinothalamic, spinoreticular, and spinomesen-cephalic tracts and inter-neurons in the spinal cord (13).
The nociceptors may be stimulated by compression, stretching, or a physical or chemical insult, and the painful stimulus is then transmitted. Noxious chemicals such as bradykinin result from inflammation, anoxia, and other pain-producing stimuli, and are likely involved in initiating the pain impulses. Prostaglandins are also involved in the sensitization of nociceptors. In the dorsal horn, small-fiber afferent nociceptors release substance P, calcitonin gene related peptide, and glutamate. The second-order nociceptive neurons then project into the spinothalamic, spinoreticular, and spinomesencephalic tracts. While these thalamic-projecting neurons are stimulated by input from the rostral ventral medulla, these neurons are also inhibited by local neurons in the dorsal horn containing opioid. Thus, the pain impulse terminates in the thalamus, where conscious pain perception may be localized, and is then transmitted to the cerebral cortex, where the pain is recognized and interpreted. The limbic system, which is anatomically very close to these structures, is likely responsible for the emotional component of the pain. The junction of primary afferent fibers, second-order nociceptive neurons, and local opioid-containing neurons represents the integration of the entire system of nociceptive transmission and analgesia, serving as the basis for multiple theories including the gate control theory (6), postsynaptic inhibitory balance theory (14), and the diffuse noxious inhibitory control theory (15). Following 20
yr of intense research, the nociceptive and antinociceptive receptors can be grouped into several general classes, including opioid peptides, substance P, noradrenergic receptors, serotoninergic receptors, y-aminobutyric acid (GABA) receptors, and other peptide receptors.
Pain impulses are transmitted from the periphery via the A-5 and C fibers to the dorsal horns of the spinal cord, where substance P is the primary neurotransmitter. Spinal gating is postulated to occur in the substantia gelatinosa of the dorsal horns. Stimulation of A-5 and C fibers within the dorsal horn has been shown to be reduced by opioid peptides or endogenous endorphins. The endogenous endorphins include met-enkephalin, dynorphin, and P-endorphin. Opioids have been shown to diminish the neuronal activity evoked by somatic and visceral stimuli, proven to cause pain in animals (16). The action of opioid peptides is always inhibitory on target neurons. Opioid receptors in the superficial dorsal horn have synaptic contacts with spinothalamic tract neurons (17). In fact, five distinct subclasses of endorphin receptors have been described, specifically k, a, 5, and £ receptors. The | receptors are largely responsible for analgesia by most natural and several synthetic opiates. Agonist-antagonist opiate analgesics tend to block the | receptor and stimulate the k receptor, which produces spinal analgesia. Stimulation of the a receptor results in the undesirable effects of opioid administration, notably dysphoria, hallucinations, and vasomotor stimulation. Enkephalins are located in the dorsal horn, periaqueductal gray, and nucleus raphe magnus, and bind to k, and 5 receptors (18). Small-diameter, high-threshold primary afferent fibers of the spinothalamic tract, spinoreticular tract, and spinomesencephalic tract have been shown to contain large numbers of presynaptic enkephalin-binding sites. The enkephalins inhibit neuronal activity in dorsal root ganglia and reduce the terminal activity of the primary afferent neurons (19). Enkephalins and enkephalin agonists have demonstrated naloxone-reversible inhibition of substance P release from primary afferent neurons (20).
Dynorphins are found in the hypothalamus, periaqueductal gray, and the spinal dorsal horn, where they bind to k receptors (21). The dynorphin levels within the dorsal root neurons increase significantly in the setting of peripheral inflammation (22). k agonists have been shown to produce analgesia, and are most responsive to mechanical and low-intensity thermal stimulation.
Substance P is synthesized in the cell bodies of small cells (type B) of spinal ganglia and is found in C-fiber primary sensory neuron cell bodies. Substance P is not released during stimulation of A-P fibers. More than half of the quantity of substance P produced is transported in a peripheral direction (23). Protracted pain states, particularly those associated with chronically inflamed or injured tissues, result in an augmented peripheral release of active factors. In the presence of substance P, there is a substantial increase in the release of several different neurotransmitters in the dorsal horn of the spinal cord. Substance P facilitates nociceptive transmission in neurons activated by noxious cutaneous stimuli. It also promotes nocicep-tive transmission by enhancing the effectiveness of other neurotransmitters through slow progressive depolarization in the dorsal horn neurons (24). Because substance P has receptors both centrally and peripherally, axonal reflexes can trigger the peripheral release of substance P causing degranulation of mast cells, plasma extravasation, and vasodilatation (25).
Both ar and a2-noradrenergic receptors are located in the descending antinociceptive pathway. Noradrenergic transmitters are found in cerebrospinal fluid and are located within the axonal terminals of interneurons making synapses with spinothalamic tract neurons involved in nociception. Both pre-synaptic and postsynaptic noradr-energic terminal connections are found in neurons responsible for nociception. The presynaptic binding is avid on small-diameter, high-threshold (nociceptive) primary afferents. a2-Noradrenergic transmitter release is inhibitory to nociceptive transmission and critical for opioid-induced analgesia (26). In fact, the application of norepinephrine to the dorsal horn will produce analgesia. The locus ceruleus in the pons is the key part of the noradrenergic pathway in the neural control of antinociception of the brain and spinal cord, sending inhibitory axons containing norepinephrine to the periaqueductal gray and to dorsal horn neurons (27).
Nociceptor sensitization is also a result of the actions of multiple second messenger systems, activated by the release of inflammatory mediators such as bradykinin, prostaglandins, serotonin, and histamine. Serotonin creates an activation pathway in the descending system of antinociception, located in the descending axons of the nucleus raphe magnus neurons. The serotoninergic axons make axosomatic and axodendritic connections on receptors on the spinal cord. Although there is significant pre-synaptic binding of serotonin on small primary afferent neurons, there is no significant decrease in the release of substance P.
A prominent excitatory response to glutamate is present in motor horn and dorsal horn cells, which are activated by the larger myelinated A-P fibers (28). Both glutamate and aspartate are associated not only with synapses of small-diameter primary afferents but also with larger diameter afferents. The dorsal horn neurons contain a large pool of glutamate, where postsynaptic activation of the dorsal horn nociceptive neurons occurs, and includes a large number of receptors for both the released peptides as well as for the excited amino acids. The amino acid receptors affect central and peripheral neuropathic pain transmission more than the nociceptive transmissions of tactile or thermal stimuli (29).
Major functions of the periaqueductal gray include pain, analgesia, fear, anxiety, vocalization, and cardiovascular control. The foremost intrinsic circuit of the periaqueductal gray is the GABA receptor network. The GABAergic system is critical to ascending pain transmission, and is responsible for receiving afferents from all of the nociceptive neurons in the spinal cord, and has projections to the thalamic nuclei and other nociceptor sites. GABA is another transmitter that acts primarily as an inhibitor to stop the outflow neuron in the descending nociceptor pathway. However, GABA can also function as a major excitatory neurotransmitter in the CNS. GABA found in the dorsal horn likely causes inhibition of small-diameter primary afferents. Receptors for GABA on inter-neurons may cause inhibition of second-order nociceptors as well as inhibition of thalamic-projecting neurons (30). Nociceptors have been demonstrated to become excited with inflammation and other pathologic conditions (31). Adenosine triphosphate (ATP) and GABA are coreleased in 70% of GABAergic neurons, which may help to explain a possible reversible switch between the inhibitory and excitatory roles of a given synapse without anatomic reorganization of the neural circuitry.
Despite the complex interaction of numerous neural pathways, the medications used in spinal injection procedures result in a simple localized effect. Certainly, given the fact that the biological activity of medications used in spinal injection procedures last far longer than the chemical activity of the agent, the entire pain production pathway is affected with drug administration. The method by which the pharmacologic agent is introduced into the tissues also plays a critical role in its clinical effect, bioavailability, duration of action, elimination, and potential adverse effects.
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