1. Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, and
2. Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden
3. Department of Medical Laboratory Sciences and Technology, Division of Clinical Neurophysiology, Huddinge University Hospital, Karolinska Institute, S-14186 Huddinge, Sweden
4. These authors contributed equally to this work

Correspondence to: Patrik Ernfors¹ Correspondence and requests for material should be addressed to P.E. (e-mail: Email: patrik@cajal.mbb.ki.se).

Neuropeptide Y (NPY) is believed to exert antinociceptive actions by inhibiting the release of substance P and other 'pain neurotransmitters' in the spinal cord dorsal horn^{1, 2, 3}. However, the physiological significance and potential therapeutic value of NPY remain obscure⁴. It is also unclear which receptor subtype(s) are involved. To identify a possible physiological role for the NPY Y1 receptor in pain transmission, we generated NPY Y1 receptor null mutant (Y1^-/-) mice by homologous recombination techniques. Here we show that Y1^-/- mice develop hyperalgesia to acute thermal, cutaneous and visceral chemical pain, and exhibit mechanical hypersensitivity. Neuropathic pain is increased, and the mice show a complete absence of the pharmacological analgesic effects of NPY. In the periphery, Y1 receptor activation is sufficient and required for substance P release and the subsequent development of neurogenic inflammation and plasma leakage. We conclude that the Y1 receptor is required for central physiological and pharmacological NPY-induced analgesia and that its activation is both sufficient and required for the release of substance P and initiation of neurogenic inflammation.