Opioids can induce
hyperalgesia in humans and in animals. Mechanisms of
opiate-induced
hyperalgesia and possibly of spinal antinociceptive tolerance may be linked to pronociceptive adaptations occurring at multiple levels of the nervous system including activation of descending facilitatory influences from the brainstem, spinal neuroplasticity, and changes in primary afferent fibers. Here, the role of
NK-1 receptor expressing cells in the spinal dorsal horn in
morphine-induced
hyperalgesia and spinal antinociceptive tolerance was assessed by ablating these cells with
intrathecal injection of SP-
saporin (
SP-SAP). Ablation of
NK-1 receptor expressing cells prevented (a)
morphine-induced thermal and mechanical
hypersensitivity, (b) increased touch-evoked spinal FOS expression, (c) upregulation of spinal
dynorphin content and (d) the rightward displacement of the spinal
morphine antinociceptive dose-response curve (i.e., tolerance).
Morphine-induced
hyperalgesia and antinociceptive tolerance were also blocked by spinal administration of
ondansetron, a serotonergic receptor antagonist. Thus,
NK-1 receptor expressing neurons play a critical role in sustained
morphine-induced neuroplastic changes which underlie spinal excitability reflected as thermal and tactile
hypersensitivity to peripheral stimuli, and to reduced antinociceptive actions of spinal
morphine (i.e., antinociceptive tolerance). Ablation of these cells likely eliminates the ascending limb of a spinal-bulbospinal loop that engages descending facilitation and elicits subsequent spinal neuroplasticity. The data may provide a basis for understanding mechanisms of prolonged
pain which can occur in the absence of tissue injury.