Role of spinal opioid receptor on the antiallodynic effect of intrathecal nociceptin in neuropathic rat
Introduction
Neuropathic pain develops after peripheral or central nerve injury [4], [33]. A variety of clinical symptoms have been noted, primarily increased responsiveness to painful stimuli (hyperalgesia) and pain responses to normally innocuous stimuli (allodynia). Non-steroidal anti-inflammatory drugs are lack of effectiveness in neuropathic pain management. Moreover, opioids are not first line drugs for neuropathic pain because of lower efficacy. Thus, continuous efforts are indispensable to solve such unmet needs.
Remarkable progress has been made toward elucidating the processes of nociceptive transmission, especially at the spinal level, where many receptors and transmitters modulate nociception [5]. Of particular interest is nociceptin (orphanin FQ), a 17-amino-acid neuropeptide identified in 1995 [18], [21]. The role of the NOP receptor (previously known as opioid receptor-like 1 receptor, ORL1) in modulating nociception in the spinal cord has recently been emphasized [15], [31]. Several studies have demonstrated that intrathecal nociceptin can act through NOP receptor in the spinal cord to produce antinociceptive effects in various painful conditions [3], [6], [9], [13], [14], [24], [26], [27]. Furthermore, the antihyperalgesic effect of intrathecal nociceptin in diabetic and mononeuropathic states was suppressed by intrathecal naloxone [3]. These findings suggest that opioid receptors may also be involved in the mechanism of action of nociceptin at the spinal level. However, the roles of the spinal opioid receptor types in the actions of nociceptin remain to be determined.
In this study, we investigated the effects of intrathecal nociceptin in a rat model of neuropathic pain following spinal nerve ligation and investigated the contribution of spinal opioid receptor types to the effect of nociceptin. In addition, the levels of opioid receptor proteins in the spinal cord were measured by Western blot analysis.
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Materials and methods
The studies were conducted after review and approval by the Institutional Animal Care and Use Committee of Chonnam National University. Male Sprague-Dawley rats weighing 100–200 g were used. They were acclimated to the standard laboratory environment (22 °C ± 0.5 °C, with a 12-h light/dark cycle) and were given standard rat chow and tap water ad libitum.
Neuropathic pain was evoked by spinal nerve ligation (left L5 and L6), as previously described [12]. The paw withdrawal threshold in response to
Results
The motor function, evaluated by the righting and the place-stepping reflexes, was normal after intrathecal administration of nociceptin at the highest dose used in this study. Both pinna and corneal reflexes were also normal at the same dose of intrathecal nociceptin.
Intrathecal nociceptin dose-dependently increased the withdrawal threshold to von Frey filament application to the ligated paw (Fig. 1).
The antiallodynic effect of intrathecal nociceptin was antagonized by intrathecal CTOP,
Discussion
The results of this study demonstrated that intrathecal nociceptin attenuated spinal nerve ligation-induced neuropathic pain in a dose-dependent manner. The antiallodynic effect of nociceptin was reversed by intrathecal naloxone. A previous study also reported that antinociceptive effect intrathecal nociceptin in neuropathic pain was suppressed by intrathecal naloxone [3].
Following a nerve injury, peripheral nerves exhibit spontaneous and persistent afferent discharges, leading to sensitization
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