Abstract
Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.
Highlights
In addition to motor and visceral dysfunction, a serious consequence of spinal cord injury (SCI) is chronic pain
The goal of the current study is to evaluate the effect of blocking fatty acid amide hydrolase (FAAH) with the inhibitors URB597 and PF-3845 on below-level cutaneous hypersensitivity SCI rats
Decreased tissue levels of oleoyl ethanolamide (OEA) and PEA were observed at the epicenter and tissue caudal to the epicenter in SCI rats
Summary
In addition to motor and visceral dysfunction, a serious consequence of spinal cord injury (SCI) is chronic pain. Below-level neuropathic pain is challenging to treat in that adverse side effects of commonly prescribed neuropathic pain analgesics may exacerbate existing dysfunctions, such as urinary retention with antidepressants and constipation with opioids. A number of studies have shown that activation of the cannabinoid (CB) receptor leads to a robust antinociception in a variety of preclinical pain models [3]. The antinociceptive effects of nonselective CB receptor agonists in rats are blocked with either cannabinoid receptor type-1 (CB1) or cannabinoid receptor type-2 (CB2) receptor antagonists. Limited clinical evidence and SCI patient survey suggests that CB receptor activation with CB ligands derived from Cannabis sativa reduces SCI pain [4,5]. The psychological and physiological effects of CB agonists are blocked by treatment with the CB1 receptor antagonist rimonabant (SR141719A) indicating the importance of CB1 receptors in mediating the effects of CB [6]
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