Anatomy, physiology and pharmacology of pain

Nociception is conveyed from the periphery to the brain at three levels: the peripheral nociceptor, the spinal cord, and the supra-spinal (brain) levels. Physiological (first or 'fast') pain is produced by stimulation of high threshold thermo/mechanical nociceptors, which transmit via fast conducting myelinated A delta fibres. These enter the dorsal horn of the spinal cord and synapse at laminae I and V. Pathophysiological (second or 'slow') pain originates from stimulation of the high threshold polymodal nociceptors (free endings) present in all tissues. The nociceptors respond to mechanical, chemical and thermal stimuli and are transmitted via slow conducting unmyelinated C fibres. These synapse at laminae II and III (substantia gelatinosa) of the dorsal horn. The second order neurons are either nociceptive specific (substantia gelatinosa) or wide dynamic range (WDR) neurons (in laminae V and VI) that respond to a wide range of noxious and non-noxious input. Both pathways ascend up the spinal cord via the spinothalamic tracts to the thalamus, which synapse and project on to the somatosensory cortex. Inhibitory inter-neurons in the substantia gelatinosa prevent activation of the dorsal root ganglia. Interneurons can be activated by A beta and inhibited by A beta and C fibre activity. Pain can be 'gated-out' by stimulating the large A beta fibres in the painful area. This is the working mechanism behind transcutaneous electrical nerve stimulation. The descending inhibition pathways originate at the level of the cortex and thalamus, and descend via the brainstem (periaqueductal grey) and the dorsal columns to terminate at the dorsal horn of the spinal cord. Neurotransmitters noradrenaline, serotonin (5-HT) and the endogenous opioids are released to provide antinociception.