Sensory Pathways and GABA

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The transmission and perception of pain are complex processes involving both the central and peripheral nervous systems. In general, pain impulses are generated, propagated, and sustained by the liberation of various autocoids, ions, and neurotransmitters at various points between the site of tissue damage, along the afferent sensory fibers, and within the spinal cord and brain. Some endogenous agents, including adenosine and a variety of neuro-peptides, are responsible for initiating, amplifying, and transmitting the pain impulse, whereas others, such as opioids, tend to be mitigating. Given the widespread distribution of GABAergic neurons, activation of this transmitter system may either enhance or reduce the propagation of pain impulses.

Nociceptive primary afferent neurons, in particular A-d and C fibers, are responsible for transmitting the pain impulse from peripheral structures to the spinal cord. Damage due to thermal, mechanical, or chemical injury causes the release of various substances from the traumatized tissue including proteolytic enzymes responsible for liberating bradykinin from gamma globulins. Adenosine, potassium, and bradykinin stimulate chemosensitive nociceptors, initiating the pain impulse and inducing the release of substance P

and prostaglandins from these nerve endings and nearby tissues. Substance P, in turn, causes the liberation of histamine from mast cells in the affected area. Similar to bradykinin, histamine and some prostaglandins, such as PGE2, are pronociceptive agents that can directly stimulate or sensitize C fibers. Hyperalgesia occurs with the continued presence of these pain-producing substances in the vicinity of the nociceptive afferent terminals.

The afferent peripheral nociceptors, which are located in the lateral portion of the dorsal root, enter the spinal cord and synapse in the marginal zone and substantia gelatinosa of the dorsal horn. These regions contain cell bodies of the secondary neurons that project to higher levels (Eisenach, 1999) (Fig. 3). Glutamic acid and substance P are the two major excitatory neurotransmitters released at this synapse. At this level, the pain impulse

Gaba Pathway

FIGURE 3 Anatomical localization of GABA receptors in the central and peripheral nervous systems. Depicted in the inset is the circuitry within the dorsal horn of the spinal cord. Abbreviations: CTX, primary sensory cortex; TH, thalamus; AMY, amygdala; PAG, periaque-ductal gray; LPBN, lateral parabrachial nucleus; NRM, medullary raphe nucleus; SC, spinal cord; PAN, primary afferent nociceptor C and A-d fibers; DIN, descending inhibitory neuron; GABA, GABAergic interneuron; ENK, enkaphalinergic interneuron; STT, spinothalamic tract projection; GABAA, GABAA receptor; GABAB, GABAB receptor.

FIGURE 3 Anatomical localization of GABA receptors in the central and peripheral nervous systems. Depicted in the inset is the circuitry within the dorsal horn of the spinal cord. Abbreviations: CTX, primary sensory cortex; TH, thalamus; AMY, amygdala; PAG, periaque-ductal gray; LPBN, lateral parabrachial nucleus; NRM, medullary raphe nucleus; SC, spinal cord; PAN, primary afferent nociceptor C and A-d fibers; DIN, descending inhibitory neuron; GABA, GABAergic interneuron; ENK, enkaphalinergic interneuron; STT, spinothalamic tract projection; GABAA, GABAA receptor; GABAB, GABAB receptor.

traveling along afferent C and A-d fibers predominantly activates spinotha-lamic neurons that compose the anterolateral component of the somato-sensory projection system. The neospinothalamic tract portion of this projection targets the ventroposterior thalamus and the primary sensory cortex, providing the major discriminative and sensory aspects of pain sensation. Paleospinothalamic projections, in contrast, diffusely target a number of brain regions, including the lateral reticular formation, the superior colliculus, the periaqueductal gray, the pons, and the amygdala (Fig. 3). These influences on higher brain centers are responsible for many of the autonomic, motivational, and affective responses to pain.

Besides receiving input from the afferent limb of the anterolateral system, the periaqueductal gray of the midbrain and the periventricular gray of the thalamus receive efferent inputs from both the hypothalamus and cerebral cortex. Neurons from the periaqueductal gray and periventricular gray project to the medullary raphe nucleus that, in turn, sends descending serotonergic projections to the dorsal horn of the spinal cord (Eisenach, 1999) (Fig. 3). Other bulbospinal projections include a noradrenergic pathway that arises in the pons. Both descending serotonergic and noradrenergic neurons, which travel as part of the dorsolateral funiculus, inhibit or facilitate pain transmission at the level of the dorsal horn.

GABAergic neurons, as well as GABAA and GABAB receptors, are present in spinal cord and brain areas associated with the mediation and perception of pain (Fig. 3). With regard to higher brain regions, there is evidence that activation of GABAA receptors in the parafasiculus thalami induces an antinociceptive response (Reyes-Vazquez et al., 1986). Moreover, there are GABAergic projections from the ventral tegmental area and sub-stantia nigra to the ventrolateral periaqueductal gray and dorsal medullary raphe nucleus that regulate the behavioral and physiological responses to pain (Kirouac et al., 2004). There are also data indicating that GABAa receptors are located on inhibitory neurons projecting from the rostral ventral medulla to the dorsal horn (Gilbert and Franklin, 2001). Local injection of a GABA agonist into this region facilitates transmission of a pain impulse through the spinal cord. In contrast, an increase in overall GABAergic activity in the rostral agranular insular cortex induces analgesia by enhancing the descending inhibition of spinal cord nociceptive neurons (Jasmin et al., 2003). However, selective activation of GABAb receptors in the same area produces hyperalgesia, perhaps by way of projections to the amygdala (Jasmin et al., 2003).

In the spinal cord there are GABA receptors located in the dorsal horn on pre- and postsynaptic sites in the region of the A-d and C fiber synapses (Yang et al., 2002) (Fig. 3). GABAb receptors are located on laminae I and II of the dorsal horn, the site of the first synapse in the pain pathway encompassing the terminal beds of small diameter, nociceptive-specific primary afferent neurons (Hokfelt et al., 1975; Price et al., 1984). Activation of presynaptic GABAb receptors on substance P or glutamate, containing neurons tends to enhance the pain threshold by inhibiting the release of these transmitters (Malcangio and Bowery, 1994). Thus, stimulation of GABAB receptors located presynaptically on the descending inhibitory sero-tonergic or noradrenergic terminals may lower the pain threshold by diminishing the release of transmitter from these cells (Yang et al., 2002). Likewise, direct GABAa or GABAb receptor-mediated inhibition of opi-oid-containing neurons tends to facilitate pain transmission by reducing the release of this endogenous analgesic (Mahmoudi and Zarrindast, 2002). It is also possible that activation of some GABA receptors indirectly influences the transmission of pain by causing hyperpolarization of inhibitory neurons thereby releasing a brake on afferent or efferent cells critical for transmitting or attenuating the impulse.

Both types of GABA receptors have been identified on primary afferent A-d and C fibers (Carlton et al., 1999; Desarmenien et al., 1984). Activation of the GABAA sites causes depolarization, whereas stimulation of the GABAB axonal receptors shortens the calcium component of the action potential. While the physiological role of these receptors is unclear, they may be of pharmacological importance by contributing to the overall response to systemically administered GABA receptor agonists.

Although activation of GABA receptors in localized regions of the brain and spinal cord can have variable effects on the pain threshold, generalized activation of either GABAA or GABAB receptors typically yields an antino-ciceptive response (Kendall et al., 1982; Levy and Proudfit, 1977; Malan et al., 2002; Sands et al., 2003; Shafizadeh et al., 1997; Smith et al., 1994; Thomas et al., 1996; Vaught et al., 1985; Zorn and Enna, 1985a). This suggests that, on balance, GABA receptor systems tend to inhibit the propagation of pain impulses. Further evidence for this is provided by the loss of GABA-containing neurons, GABA transporters, and GABAergic activity in the spinal cord in animal models of neuropathic pain or following spinal cord injury (Drew et al., 2004; Ibuki et al., 1997; Miletic et al., 2003; Moore et al., 2002; Somers and Clemente, 2002). While it has been speculated that this decline in GABAergic function is responsible, in part, for the persistent pain and allodynia seen in these conditions, others suggest this may not be the case (Polgar et al., 2003).

Taken together, these reports indicate that GABAergic neurons and receptors are located in regions of the central nervous system that are critical for transmitting and perceiving many aspects of pain. Given its widespread distribution, GABAergic transmission facilitates the transmission of pain impulses in some areas and inhibits it in others. Inasmuch as the sensitivity of pain pathways is altered over time through the process of central sensiti-zation (Attal and Bouhassira, 1999; Ossipov et al., 2000), it is likely that the response to GABAergic agents may vary as a function of when they are administered relative to the initial insult.

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