Potentiation of Morphine Antinociception and Inhibition of Diabetic Neuropathic Pain by the Multi-chemokine Receptor Antagonist Peptide RAP-103

Aims: We determined the ability of the multi-chemokine receptor (CCR2/CCR5/CCR8) antagonist RAP-103 to modulate pain behaviors in an acute model of surgical pain, with and without an added opioid (morphine), and by itself in a chronic model of Streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN).

Materials And Methods: Pain behaviors were assessed by mechanical and thermal tests in rats. Cytokine and chemokine biomarkers in sciatic nerve and spinal cord were assessed by in situ qPCR.

Key Findings: In the incisional pain assay, RAP-103 (0.01-1 mg/kg, i.p.) alone had no antiallodynic effect post-surgery. RAP-103 (0.5 mg/kg) when co-administered with morphine (0.5-5 mg/kg), reduced the ED of morphine from 3.19 mg/kg to 1.42 mg/kg. In a DPN model, rats exhibited persistent mechanical and cold allodynia. Oral administration of RAP-103 (0.5-0.02 mg/kg/day) resulted in a complete reversal of established hypersensitivity in DPN rats (P < .001), which gradually returned to pain hypersensitivity after the cessation of the treatment. The mRNA expression of cytokines, IL-1β, TNFα; chemokines CCL2, CCL3; and chemokine receptors CCR2 and CCR5 in DPN rat sciatic nerve, but not spinal cord, were significantly increased. RAP-103 resulted in significant reductions in sciatic nerve expression of IL-1β, TNFα and CCL3 in STZ-induced diabetic rats with trends toward lower levels for CCL2 and CCR5, while CCR2 was unchanged.

Significance: In acute pain, co-administration of RAP-103 with morphine provided the same antinociceptive effect with a reduced dose of morphine, reducing opioid side-effects and risks. RAP-103 by itself is an effective non-opioid antinociceptive treatment for diabetic neuropathic pain.