Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation

Abstract

Chemokine signaling is important in neuropathic pain, with microglial cells expressing CCR2 playing a well-established key role. DAPTA, a HIV gp120-derived CCR5 entry inhibitor, has been shown to inhibit CCR5-mediated monocyte migration and to attenuate neuroinflammation. We report here that as a stabilized analog of DAPTA, the short peptide RAP-103 exhibits potent antagonism for both CCR2 (half maximal inhibitory concentration [IC50] 4.2 pM) and CCR5 (IC50 0.18 pM) in monocyte chemotaxis. Oral administration of RAP-103 (0.05-1 mg/kg) for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia after partial ligation of the sciatic nerve in rats. Administered from days 8 to 12, RAP-103 (0.2-1 mg/kg) reverses already established hypersensitivity. RAP-103 relieves behavioral hypersensitivity, probably through either or both CCR2 and CCR5 blockade, because by using genetically deficient animals, we demonstrated that in addition to CCR2, CCR5 is also required for the development of neuropathic pain. Moreover, RAP-103 is able to reduce spinal microglial activation and monocyte infiltration, and to inhibit inflammatory responses evoked by peripheral nerve injury that cause chronic pain. Our findings suggest that targeting CCR2/CCR5 should provide greater efficacy than targeting CCR2 or CCR5 alone, and that dual CCR2/CCR5 antagonist RAP-103 has the potential for broad clinical use in neuropathic pain treatment.

CC‐chemokine ligand 4/macrophage inflammatory protein‐1β participates in the induction of neuropathic pain after peripheral nerve injury

“…Similar results were seen in our earlier study showing that knockdown of CCR5 in the SCN using siRNA prevented both allodynia and hyperalgesia (Kiguchi et al, 2010b). Consistent with our findings, recent report showed that neuropathic pain after nerve ligation were not elicited in CCR5 knockout mice (Padi et al, 2012). These lines of evidence confirm that MIP-1b mainly participates in tactile allodynia after nerve injury.…”

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance)

“…Of the 44 genes in the GO Axon Extension and GO Regulation of Axonogenesis overlap set (Supplemental Table 7), a number have been implicated in neuropathy, including hereditary neuropathy genes ( MAP1B 46 , NGF 47 , FXN 48 ), genes with variants or expression signatures associated with diabetic or HIV-induced peripheral neuropathy ( APOE 49, 50 , MAPT 51 , CDH4 51 ), genes involved in neurological pain pathways ( MT3 52 , TRPV2 53 , CCR5 54 , CXCL12 55 ), and genes involved in response to or repair/prevention of peripheral nerve damage ( RYK 56 , SLIT1 57 , NTRK3 58 , NGF 59, 60 , TRPV2 53 , NTN1 61 , NDEL1 62 ). The majority (38) of these 44 genes fall in the GO term Regulation of Axon Extension (GO 0030516), which is a subset of both GO Regulation of Axonogenesis and GO Axon Extension.…”

Emerging targets in neuroinflammation-driven chronic pain

“…To potentially increase the efficacy of chemokine antagonism it might be beneficial to simultaneously target several chemokine receptors. Indeed the dual CCR2/CCR5 peptide antagonist RAP-103 (which was orally active) effectively reduced neuropathic pain and inhibit CCR2- and CCR5-mediated monocyte chemotaxis and inflammation in rodents 94 .…”