Chemokines and glycoprotein 120 produce pain hypersensitivity by directly exciting primary nociceptive neurons

Human immunodeficiency virus-1 (HIV-1) infection is associated with numerou s effects on the nervous system, including pain and peripheral neuropathies . We now demonstrate that cultured rat dorsal root ganglion (DRG) neurons e xpress a wide variety of chemokine receptors, including those that are thou ght to act as receptors for the HIV-1 coat protein glycoprotein120 (gp120). Chemokines that activate ail of the known chemokine receptors increased [C a2+](i) in subsets of cultured DRG cells. Many neurons responded to multipl e chemokines and also to bradykinin, ATP, and capsaicin. Immunohistochemica l studies demonstrated the expression of the CXCR4 and CCR4 chemokine recep tors on populations of DRG neurons that also expressed substance P and the VR1 vanilloid receptor. RT-PCR analysis confirmed the expression of CXCR4, CX3CR1, CCR4, and CCR5 mRNAs in DRG neurons. Chemokines and gp120 produced excitatory effects on DRG neurons and also stimulated the release of substa nce P. Chemokines and gp120 also produced allodynia after injection into th e rat paw. Thus these results provide evidence that chemokines and gp120 ma y produce painful effects via direct actions on chemokine receptors express ed by nociceptive neurons. Chemokine receptor antagonists may be important therapeutic interventions in the pain that is associated with HIV-1 infecti on and inflammation.