Abstract
Objective: Oxytocin (OT) is synthesized within the paraventricular nucleus and supraoptic nucleus of the hypothalamus. In addition to its role in uterine contraction, OT plays an important antinociceptive role; however, the underlying molecular mechanisms of antinociceptive role of OT remain elusive. We hypothesized that the antinociceptive effect of OT on neuropathic pain may occur via inhibition of TRPV1 activation in the spinal cord. The present study explores the antinociceptive role of OT and its mechanisms in neuropathic pain.Methods: Partial sciatic nerve ligation (pSNL) was performed to induce neuropathic pain. Animal behaviors were measured using a set of electronic von Frey apparatus and hot plate. Electrophysiological recordings and molecular biological experiments were performed.Results: Intrathecal administration of OT alleviated both mechanical allodynia and thermal hyperalgesia in pSNL rats (n = 6, per group, P < 0.0001, saline vs. OT group). Electrophysiological data revealed that OT significantly inhibited the enhancement of frequency and amplitude of spontaneous excitatory post-synaptic currents induced presynaptically by TRPV1 activation in the spinal cord. Moreover, the inhibitory effect of OT on capsaicin-induced facilitation of excitatory transmission was blocked by co-treatment with saclofen, while intrathecal administration of OT dramatically inhibited capsaicin-induced ongoing pain in rats, (n = 6, per group, P < 0.0001, saline vs. OT group). The paw withdrawal latency in response to heat stimulation was significantly impaired in TRPV1KO mice 3 days after pSNL upon OT (i.t.) treatment, compared with wild type mice (n = 6, P < 0.05). Finally, OT prevented TRPV1 up-regulation in spinal cords of pSNL model rats.Conclusion: OT relieves neuropathic pain through GABA release and presynaptic TRPV1 inhibition in the spinal cord. OT and its receptor system might be an intriguing target for the treatment and prevention of neuropathic pain.
Highlights
Neuropathic pain is a major public health concern due to its considerable impact on patients’ quality of life
We found that OT relieved neuropathic pain through GABA release and presynaptic Transient receptor potential channel vanilloid 1 (TRPV1) inhibition in the spinal cord, which further affected the behavior in neuropathic pain model rats
OT concentrations in cerebrospinal fluid (CSF) were significantly increased in rats from the first day after partial sciatic nerve ligation (pSNL) (Figure 1C; n = 6 per group; F = 8.396, P < 0.0001, repeated analysis of variance (ANOVA)), peaking on the third day after pSNL from the initial 2.01 ± 0.24 to 5.18 ± 0.40, indicating a physiological increase of OT levels in CSF upon peripheral nerve injury
Summary
Neuropathic pain is a major public health concern due to its considerable impact on patients’ quality of life. For example in animal models, with neuropathic pain, intrathecal delivery of OT has been shown to be a significant analgesic (Miranda-Cardenas et al, 2006; Yang et al, 2007), while in animal models with inflammatory pain, OT release from parvocellular OT neurons suppresses nociception and promotes analgesia (Eliava et al, 2016). Systemic administration of OT produces analgesia in thermal, mechanical, and inflammatory stimulation (Schorscher-Petcu et al, 2010), and alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors in rat trigeminal ganglia (Kubo et al, 2017). These studies provide promising evidence for antinociceptive action of OT. Understanding the analgesic mechanisms of OT may offer a potentially novel avenue for treating neuropathic pain
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