Cellular Minipumps for the Treatment of Pain
Chronic neuropathic pain following damage to the peripheral or CNS has been difficult to treat clinically (14). As an illustration of the severity of pain following spinal cord injury (SCI), patients often report pain, rather than immobility, as the major deterrent to good quality of life (15). Pharmacological pain management is based on nonopioid and opioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase 2 (COX-2) inhibitors (16), calcium channel blockers (17), capsaicin (18), nicotine receptor agonists (19), and opioids (20) (e.g., morphine and its derivatives). Adjunct drugs, such as antidepressants and anticonvulsants, often accompany more antinociceptive agents in certain types of pain, like diabetic neuropathy (21). Gabapentin, an anticonvulsant, has become the most common medication for SCI pain (22), probably owing to its calcium channel-blocking functions (23). Combination of medications, such as NSAIDs with opioids, seems to be more effective in malignant pain that is associated with cancer (24). However, the potential abuse of many of these agents, especially opioids, remains a major societal problem (25). Oral administration is the favored route for all these drugs, but with the development of interfering side effects, intrathecal administration (26) (often by implanted mechanical pumps for long-term delivery; 27) can be used. The intrathecal route has often been used for drugs in animal studies (28,29) to limit the area of application and dosage for optimum antinociception without side effects. From the initial use of cell grafts for pain (30), the intrathecal placement of transplants was preferred, as cells in the intrathecal space can act as "cellular minipumps," which are able to release neuroactive antinociceptive molecules to affect spinal pain-processing centers in the dorsal horn.
Other potential interventive agents for the treatment of pain are based on current and developing strategies elucidated from recent research, especially concerning "central spinal sensitization" and the spinal mechanisms thought to be the origins and ongoing causes of chronic pain (31), even when the injury is peripheral in location (32). For example, persistent small afferent input, as generated by tissue or nerve damage, results in a hyperalgesia at the site of injury and a tactile allodynia in areas adjacent to the site. Hyperalgesia is the result of sensitization of the peripheral terminal and a central (or spinal) facilitation evoked by persistent small afferent input. The allodynia reflects a central sensitization, with excitatory neurotransmitter (e.g., glutamate and substance P) release, initiating a cascade of downstream events, such as release of nitric oxide (NO), various COX products, and activation of several key kinase enzymes. Specific receptors mediate the initial events, i.e., through the N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors and neurokinin 1 substance P receptors. Specific activation of these receptors enhances prostaglandin E2 release, which then facilitates further release of spinal amino acids and peptides. Activation of specific receptors (|/A opioid, a2 adrenergic, and neuropeptide Y) on spinal C fiber terminals prevents release of primary afferent peptides and spinal amino acids and blocks acute and facilitated pain states. In contrast, glutamate receptor antagonists, COX-2, and NO synthase inhibitors only act to diminish hyperalgesia. Spinal delivery of some of these agents diminishes human injury pain states, suggesting that such preclinical mechanisms may reflect the induction of some types of neuropathic pain.
Thus far, the vast majority of cellular transplantation approaches for chronic pain management have utilized the cellular minipump method. However, it is possible to envision a cellular replacement strategy for more severe cases of chronic pain consequent to injury of the spinal cord. For example, a likely candidate for this type of strategy may be the particularly vulnerable dorsal horn inhibitory interneurons, which are thought to restrict ongoing pain under normal circumstances. The barrage of activity in damaged primary afferents and excessive excitatory amino acid release may result in excitotoxic insult to these small inhibitory interneurons in the spinal cord (33). In support of this theory, an increased incidence of hyperchro-matic "dark neurons" in the superficial spinal or medullary dorsal horn is found following peripheral nerve injury, and this can be further exacerbated by pharmacologic blockade of inhibitory neurotransmission (34,35). Coinciding with the rise of dark neurons in these areas are spontaneously active neurons, as well as neurons with expanded receptive fields—those that respond to nonnoxious stimulation of adjacent dermatomes (36,37). Dark neurons may be indicative of trans-synaptic degeneration or atrophy and are likely to include functionally impaired inhibitory interneurons (35,38).
y-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter found in the spinal cord that is concentrated in the superficial laminae of the dorsal horn (39,40), where sensory, particularly nociceptive, processing predominates. An important role for GABA in sensory processing is suggested by physiological and behavioral studies, which indicate primarily an inhibitory function in the transmission of noxious stimulation (41,42). Thus, it is conceivable that a loss of GABAergic inhibitory mechanisms in the spinal dorsal horn leads to sustained hyperexcitability in persistent pain states. A significant decline in laminae I-III GABA immunoreactivity (GABA-IR) was found after sciatic nerve transection (43), and reductions in both GABA-IR and GAD have been observed following chronic constriction injury (CCI) of the sciatic nerve (44-47). In addition, using TUNEL labeling, cell death in the superficial dorsal horn has been observed following CCI and sciatic neurectomy; this could be prevented by NMDA antagonists (48,49). Using stereological estimates from EM sections, excitotoxic neuronal cell death in the superficial dorsal horn was also observed in sciatic nerve-lesioned animals following stimulation of A fibers (50). The magnitude of neuronal loss and spinal reorganization is likely even further exaggerated in SCI from the severe necrosis and neuronal loss as a result of the mechanical trauma, as well as secondary neuropathology. A dramatic loss in spinal GABAergic neurons occurs after ischemic spinal injury, and GABAB agonists can reverse mechanical allodynia in the early postinjury phase (51). Preliminary findings in our laboratory have also indicated a selective loss in GABA-IR in the superficial dorsal horn following excitotoxic SCI, and transplantation of GABAergic neural stem cells into the injured dorsal horn can reverse some chronic pain symptoms following SCI (52).
In contrast with chronic pain, the majority of transplantation studies for TBI have attempted to utilize neural transplantation to replace neural elements that have been lost or damaged owing to initial trauma or secondary degeneration. Meeting this goal will be quite challenging, as it will likely require not only grafting of the appropriate complement of cell types (or potential to differentiate to appropriate cell types), but also reestablishment of proper connectivity with the intact host CNS. Nevertheless, it has been suggested that even a small (<10%) replacement of lost neurons may result in substantial functional improvement following CNS injury (53). Indeed, although overall survival of grafted cells in CNS injury models appears low, significant improvements in somatomotor and cognitive performances have been reported with a variety of transplantation interventions in the injured brain (see below for details).
In addition to transplantation approaches to replace lost cellular populations after brain trauma, several groups have refocused efforts on utilizing these grafted cells as delivery vehicles for providing therapeutic trophic molecules. Indeed, numerous studies with the initial goal of cellular replacement have revealed limited cellular differentiation to desired neuronal phe-notypes and have thus attributed beneficial behavioral outcomes to the provision of local trophic factors by the grafted cells or promotion of host trophic factor upregulation. More recent attempts at taking advantage of this potential have utilized combination strategies by engineering possible replacement cells to produce increased levels of beneficial trophic support (see below for details).
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