α2Adrenoceptor–mediated Presynaptic Inhibition of Primary Afferent Glutamatergic Transmission in Rat Substantia Gelatinosa Neurons

Abstract

Norepinephrine inhibits A delta-fiber- and C-fiber-mediated sensory transmission to substantia gelatinosa neurons through the activation of the alpha 2 adrenoceptor (possibly alpha2A type, based on the current, published behavioral and anatomical data) existing in primary afferent terminals; this action of norepinephrine is more effective in A delta-fiber than C-fiber transmission. This could contribute to at least a part of inhibitory modulation of pain sensation in the substantia gelatinosa by intrathecally administered norepinephrine.

Mechanisms for the Anti-nociceptive Actions of the Descending Noradrenergic and Serotonergic Systems in the Spinal Cord

“…The inhibitory actions of NA on the synapses between the primary afferents and dorsal horn neurons have been investigated in the DRG neurons, demonstrating a depression of the Ca 2+ current by the activation of α 2 receptors. These observations can be extrapolated to the primary afferent terminals where the activation of α 2 receptors reduces the glutamate release (45), causing a decrease in the nociceptive inputs to the dorsal horn neurons (36). This presynaptic action of NA is further confirmed in the spinal cord, while observing a presynaptic depression of the dorsal root evoked EPSCs in spinal cord slice preparations (see below) (37,45).…”

“…These observations can be extrapolated to the primary afferent terminals where the activation of α 2 receptors reduces the glutamate release (45), causing a decrease in the nociceptive inputs to the dorsal horn neurons (36). This presynaptic action of NA is further confirmed in the spinal cord, while observing a presynaptic depression of the dorsal root evoked EPSCs in spinal cord slice preparations (see below) (37,45). Recent anatomical studies have shown α 2C -adrenergic receptors to be localized on the axon terminals of excitatory interneurons in the superficial dorsal horn that come in contact with spino-medullary projection neurons, possibly contributing to noradrenergic antinociception (44).…”

“…Both Aδ and C afferent-evoked EPSCs are reversibly inhibited by NA by 20% -60% without affecting the mEPSCs. Interestingly, the Aδ afferent-evoked EPSCs are more sensitive to NA than the C-afferent-evoked one (45). Aδ afferents are believed to convey fast and confined pain; thus, NA is presumed to depress more effectively the fast pain than slow long lasting pain.…”

“…Presynaptic actions of NA: To address whether spinally administered NA acts presynaptically to alter the excitatory and inhibitory transmitter release and, if so, to identify which receptor subtype is involved, a blind patch-clamp technique to study the action of NA on miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively) in SG neurons from adult rat spinal cord slices was made (45,63,64). In the majority of SG neurons, NA dosedependently increased the frequency of GABAergic and glycinergic mIPSCs, while mEPSCs are not significantly altered in the presence of tetrodotoxin (TTX).…”

Current and Future Issues in the development of spinal agents for the management of pain

“…Interestingly, discrepancies are noted between the α 2 subtypes as defined by message and immunohistochemistry (see [91]). Spinal α 2 adrenergic receptors display several characteristics: i) binding is present presynaptically on C-fibers and postsynaptically on spinal neurons; ii) agonists are believed to alter spinal nociceptive processing by preventing opening of voltage-sensitive Ca channels (blocking release) [92,93] and increasing potassium conductance leading to hyperpolarization of dorsal horn neurons through increased pK conductance [87,88,94,95]. Consistent with their pharmacology, the analgesic activity is reversed by α 2 antagonists such as atipamezole [96][97][98].…”