Physiology of Pain


Pain has been described as a “unpleasant sensory and emotional experience”. It is influenced by biological, psychological and social factors that together form our perception of pain and its intensity. Therefore, pain is not simply inferred or described as nociception – the detection of noxious chemical, thermal or mechanical stimuli. Rather, the perception of pain is founded on the complex integration of physiologic signaling at three major levels: Transduction, Transmission and the Perception of Pain.

Pain Transduction

In its most fundamental form, the peripheral nervous system has evolved to detect noxious stimuli that signals actual or impending tissue damage. This is accomplished by the specialization of sensory neurons as primary afferent nociceptors capable of detecting noxious stimuli from somatic and visceral tissues.  Nociceptors innervate nearly all tissues in the body – less the nervous system itself and are activated through specialized channels and receptor-proteins such as the capsaicin receptor - TRPV1 (1).

Pain Transmission

Signaling the central nervous system of actual or impending tissue injury requires linking peripheral nociceptive terminals, through dorsal root or trigeminal ganglion to spinal dorsal horn and cranial nerve entry points. This step requires axonal nerve conduction propagated by voltage gated sodium channels. Interruption of transmission by local anesthetic sodium channel blockade can be utilized for anesthesia and analgesia. Subsequently, nociceptive signaling to higher centers allows for multiple sites of modulation throughout the spinal cord and midbrain.

Pain Perception

Where does the sensation and emotional experience of pain reside? Utilizing wide-ranging neural networks, our conscious awareness of pain, usually associated with cortical function is dependent and influenced by multiple brain regions. For example, distraction reduces pain through the somatosensory cortex, insula and thalamus, whereas states of hypervigilance seen with anxiety disorders and catastrophizing can produce exaggerated and/or persistent perceptions of pain. Cognitive and behavior therapies can access these pathways and help reduce and sometimes resolve disabling chronic painful perceptions (2).

Pain Modulation

Just as the perception of pain may be amplified peripherally through the production and release of inflammatory mediators arising from tissue injury, subsequent transmission and perception of pain can be positively (or negatively) modulated based on the physiologic state of the central nervous system (3). Activation of the endogenous opioid-peptide system is one example of how the nervous system functions to negatively modulate or dampen pain signaling. The central action of selective norepinephrine and serotonin reuptake inhibitors are another way to blunt or reverse painful conditions that are dependent on endogenous pain modulatory pathways.


Schumacher, M. A. (2010) Transient Receptor Potential Channels in Pain and Inflammation: Therapeutic Opportunities. Pain Pract

Tracey, I., and Mantyh, P. W. (2007) The cerebral signature for pain perception and its modulation. Neuron 55, 377-391

Woolf, C. J. (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2-15