The use of N-type voltage-gated calcium channel (CaV2.2) blockers in pain therapeutics is limited by numerous physiologic side-effects. Here we report suppression of inflammatory and neuropathic hypersensitivity by inhibiting binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2, thus reducing channel function. A peptide of CRMP-2 fused to the HIV TAT protein (TAT-CBD3) decreases neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduces meningeal blood flow, reduces nocifensive behavior induced by formalin injection or corneal capsaicin application, and reverses neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function, or depression. At doses 10-fold higher than that required to reduce hypersensitivity in vivo, a transient episode of tail kinking and body contortion was observed. By preventing CRMP-2-mediated enhancement of CaV2.2 function, TAT-CBD3 alleviates inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain. Remarkably, sympathetic-associated cardiovascular activity is not affected by TAT-CBD3. Peptide analgesics, such as TAT-CBD3 and its derivatives, with restricted access to the CNS represent a completely novel approach to the treatment of severe pain with an improved safety profile.