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Lack of analgesic efficacy of spinal ondansetron on thermal and mechanical hypersensitivity following spinal nerve ligation in the rat

Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Brain research (Impact Factor: 2.83). 09/2010; 1352:83-93. DOI: 10.1016/j.brainres.2010.07.020
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ABSTRACT The balance between descending inhibition and facilitation is thought to be disturbed in chronic pain states. Increased facilitation by spinally released serotonin has been suggested by demonstration that mechanically evoked neuronal responses of wide dynamic range neurons are inhibited by 5-HT3 receptor antagonists in rats following spinal nerve ligation (SNL) but not sham operation. Despite these physiologic data, the effects of spinal 5-HT3 receptor blockade on behavioral hypersensitivity and neurochemical alterations in spinal serotonergic system have not been thoroughly investigated following spinal nerve ligation in the rat. To test this, we acutely injected intrathecal ondansetron in rats between 14 and 30 days after SNL and assessed effects on thermal and mechanical hypersensitivity. We also determined the density of serotonergic nerve fibers, serotonin content and the levels of 5-HT3 receptors within the spinal cord at this time point. Intrathecal ondansetron (1, 3, 10, 30, and 100microg) produced no effect on behavioral measures of thermal or mechanical hypersensitivity whereas intrathecal morphine (1microg) and gabapentin (200microg) partially reversed thermal and mechanical hypersensitivity following SNL. In addition, SNL did not alter the density of serotonergic fibers or 5-HT3 receptor immunoreactivity or spinal tissue content of 5-HT within the dorsal horn. These results do not support anatomic plasticity of descending serotonergic pathways or tonic 5-HT3 receptor activity in maintaining hypersensitivity after nerve injury and in contrast to previous studies fail to demonstrate an anti-hypersensitivity effect of intrathecal injection of the 5-HT3 receptor antagonist ondansetron. Importantly, behavioral measures of mechanical hypersensitivity assess threshold responses whereas physiological studies of mechanically evoked neuronal responses involve application of suprathreshold stimuli. Thus, suprathreshold or more intense stimuli may be necessary to recruit descending serotonergic facilitatory drive required to observe the inhibitory effects of ondansetron on spinal neuronal excitability and behavioral hypersensitivity.

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Available from: Christopher M Peters, Aug 07, 2015
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    • "Interestingly, recent studies reported that intrathecal injection of 5-HT 3 receptor antagonists such as CGP35348 (Okazaki et al., 2008) or ondansetron (Peters et al., 2010) had no preventive effects on mechanical allodynia and/or thermal hyperalgesia in a rat with L5/6 SNL, which conflicts with the study with the same drug ondansetron in the same SNL model (Dogrul et al., 2009) and our results. However, we noticed that there were no expected plastic changes of both 5- HT immunoreactive intensity and 5-HT 3 receptor innervation in the lumbar spinal dorsal horn at 14 d after L5/L6 SNL in the study reported by Peters and colleagues (Peters et al., 2010). In contrast, we found a robust increase of tissue Tph-2 level in the RVM (Wei et al., 2010) at 14 d and a progressive enhancement of tissue 5-HT 3 receptor expression in the spinal dorsal horn from 1 d to 28 d following L5 SNL when compared with that in the sham group (unpublished observations). "
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    • "For instance, using in vivo electrophysiological methods, we have demonstrated a pro-nociceptive function for spinal 5-HT3 receptors on spinal neuronal activity since topical spinal application of the selective antagonist ondansetron significantly reduced spinal neuronal activity in normal and pathaphysiological conditions (Rahman et al., 2004; Suzuki et al., 2002; Suzuki et al., 2004). This pronociceptive role for spinal 5-HT3 receptors has also been borne out by behavioural and anatomical studies (Dogrul et al., 2009; Oatway et al., 2004; Svensson et al., 2006; Zeitz et al., 2002) but disputed by others (Peters et al., 2010), although a pronociceptive role of endogenous spinal 5-HT was demonstrated by the reduction in nociceptive responses following selective depletion of spinal 5-HT (Dogrul et al., 2009; Oatway et al., 2004; Rahman et al., 2006). Nonetheless, descending serotonergic facilitation may not be exclusive to 5-HT activating the 5-HT3 receptor, as there are several lines of evidence pointing to a pronociceptive role for the 5-HT2 receptor, although controversy exists. "
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