Inhibition of nociceptive responses after systemic administration of amidated kyotorphin

Abstract

BACKGROUND AND PURPOSEKyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood–brain barrier (BBB) and detract from the possible clinical use of KTP as an analgesic. In this study, we aimed to increase the lipophilicity of KTP by amidation and to evaluate the analgesic efficacy of a new KTP derivative (KTP-amide – KTP-NH2).EXPERIMENTAL APPROACHWe synthesized KTP-NH2. This peptide was given systemically to assess its ability to cross the BBB. A wide range of pain models, including acute, sustained and chronic inflammatory and neuropathic pain, were used to characterize analgesic efficacies of KTP-NH2. Binding to opioid receptors and toxicity were also measured.KEY RESULTSKTP-NH2, unlike its precursor KTP, was lipophilic and highly analgesic following systemic administration in several acute and chronic pain models, without inducing toxic effects or affecting motor responses and blood pressure. Binding to opioid receptors was minimal. KTP-NH2 inhibited nociceptive responses of spinal neurons. Its analgesic effects were prevented by intrathecal or i.p. administration of naloxone.CONCLUSIONS AND IMPLICATIONSAmidation allowed KTP to show good analgesic ability after systemic delivery in acute and chronic pain models. The indirect opioid-mediated actions of KTP-NH2 may explain why this compound retained its analgesic effects although the usual side effects of opioids were absent, which is a desired feature in next-generation pain medications.

The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: insights of a lipid-mediated mechanism

“…A suggested alternative mechanism for analgesia induced by KTP is their rapid degradation, resulting in free l-Arg, the substrate for nitric oxide (NO) synthase (Arima et al 1997). The NO thus formed would induce analgesia via metenkephalin release, which is the common final event leading to analgesia (Ribeiro et al 2011a). This data provides a hint for the relationship between the results obtained for KTP on ITC and intravital studies.…”

Pharmacological Potential of the Endogenous Dipeptide Kyotorphin and Selected Derivatives

“…Although naloxone is an opioid antagonist, studies demonstrated KTP itself does not bind to opioid receptors, but has rather an indirect action mediated by met-enkephalin and β-endorphin, which activate δ- and/or μ-opioid receptors (Takagi et al, 1979b; Rackham et al, 1982; Ribeiro et al, 2011a). Other authors confirmed KTP-induced met-enkephalin release from guinea pig and rat brain slices (Shiomi et al, 1981; Takagi et al, 1982; Janicki and Lipkowski, 1983).…”

“…In order to overcome these issues while preserving effectiveness as analgesic, several groups including ours have worked in different strategies to modify the original peptide. Some of these strategies deal with (i) chirality (Rybal’chenko et al, 1999; Lopes et al, 2006a), (ii) use of unnatural amino acids and substitution of peptide bonds (Dzimbova et al, 2014; Serrano et al, 2014b), (iii) conjugation with lipophilic groups (Chen et al, 1998; Wang et al, 2001; Lopes et al, 2006b; Ribeiro et al, 2011b; Serrano et al, 2014b), (iv) cationicity improvement (Ribeiro et al, 2011a). …”

“…In addition, KTP-NH 2 did not develop resistance unlike morphine, neither jeopardized blood pressure or motor capacity. Accordingly, the peptide showed low affinity to opioid receptors (Ribeiro et al, 2011a). …”

“…These two derivatives successfully combined lipophilicity and resistance to enzymatic degradation (Serrano et al, 2014b). Still, some derivatives with lower permeability, such as KTP-NH 2 , have previously demonstrated good analgesic efficacy (Ribeiro et al, 2011a). These results suggest that this particular derivative might have specific transporters to translocate BBB (Serrano et al, 2014b).…”