Noxious stimuli such as protons (H+), temperature (temp) etc. applied to endorgans activate nociceptors. Injury leads to the release of prostaglandins such as prostaglandin E2 (PGE2), serotonin (5-HT), nerve growth factor (NGF) etc. from damaged cells, Bradykinin (BK) from blood vessels and substance P (sP) from nociceptors. These agents either activate nociceptors directly or senstitize them to subsequent stimuli by parallel activation of intracellular kinases by G-protein coupled receptors and tyrosine kinase receptors. Primary nociceptive afferents (C-fibers, Ad-fibers) of dorsal root ganglion (DRG) neurons synapse on second order neurons (S) in the spinal dorsal horn (magnified in inset). Here, glutamate (Glu) and sP released from primary afferent terminals (A) activate glutamate receptors (NMDA R, AMPA R, mGluRs) and neurokinin-1 (NK-1) receptors, respectively, located post-synaptically on spinal neurons. These synapses are negatively modulated by spinal inhibitory interneurons (I), which employ enkephalins (Enk) or gamma-amino-butyric acid (GABA) as neurotransmitters. Spinal neurons convey nociceptive information to the brain and brainstem. Activation of descending noradrenergic and/or serotonergic systems, which originate in the brain and brainstem, leads to the activation of spinal inhibitory interneurons (I) thereby resulting in antinociception. (From http://encref.springer.de/mp/0002.htm)