At the peripheral level distinct processes were observed which characterize pathophysiologic nociceptive and neuropathic pain. The hallmark of pathophysiologic nociceptive pain, e.g., pain during inflammation or after tissue injury, is peripheral sensitization. Nociceptive nerve fibers exhibit a lowering of their excitation threshold for the response to mechanical and/or thermal stimuli and increased firing frequencies during the application of stimuli of noxious intensities. Such processes were characterized in the skin, muscle, joint, and visceral organs (Schaible and Richter 2004). Molecular mechanisms of peripheral sensitization are addressed in Sect. 1.4 (see below). More recently, the concept of hyperalgesic priming was introduced (see Kandasamy and Price 2015). Priming arises from an initial injury and results in the development of a remarkable susceptibility to normally subthreshold noxious inputs causing a prolonged pain state in primed animals. Priming increases the sensitization process which is evoked by sensitizing mediators. As an example, application of prostaglandin E2 to normal tissue causes a short-lasting sensitization of nociceptors if applied before injury or priming. However, if the neurons were primed, e.g., by interleukin-6, NGF, and other priming stimuli, prostaglandin E2 will cause a long-lasting sensitization (see Kandasamy and Price 2015).

A frequent process of neuropathic pain at the peripheral level is the generation of ectopic discharges. These action potentials can be elicited at the lesion site of the nerve fibers, but they can also be generated in the soma of the lesioned neurons (Devor 2009). Underlying mechanisms are changes in the expression of ion channels, actions of inflammatory mediators on lesioned fibers, and effects of the sympathetic nervous system on lesioned nerve fibers. In the latter case the neuropathic pain may be sympathetically maintained (Schaible and Richter 2004).

Peripheral nociceptive processes often trigger changes in the spinal cord which are called central sensitization. The changes in the spinal cord provide a gain of the nociceptive processing at the spinal site (Cervero 2009; Woolf and Salter 2000). Nociceptive spinal cord neurons which receive increased input from inflamed regions show the following phenomena: a lowering of threshold, increased responses to innocuous and noxious stimuli, and an expansion of the receptive fields (Schaible et al. 2009). In the sensitized state, more spinal cord neurons show responses to a stimulus applied to a specific peripheral site. These changes reflect an increase of the synaptic processing including the suprathreshold activation of synapses which may be too weak in the normal state to depolarize the neuron sufficiently. In many aspects these processes are similar to the long-term potentiation which was characterized as a major process of memory formation in the hippocampus (Sandkühler 2000). Central sensitization is also thought to occur in neuropathic pain states.

Several cell types may contribute to the spinal sensitization. First, the sensitization of peripheral nociceptors increases the sensory input into the spinal cord, thus providing a stronger presynaptic component of synaptic activation. Second, postsynaptic spinal cord neurons are rendered hyperexcitable by the activation of NMDA and other receptors (Sandkühler 2000; Woolf and Salter 2000). Third, glial cells may be activated and produce cytokines and other mediators which facilitate the spinal processing. Glial cells are strongly activated in neuropathic pain states, but they may also contribute to inflammatory pain (McMahon and Malcangio 2009). The involvement of glial cells in pain states is addressed by Old et al. (2015). Fourth, the activity of inhibitory interneurons may be reduced. The inhibitory neurons in the spinal cord and the mechanisms by which the inhibitory control is decreased or lost are addressed by Todd (2015). The spinal sensitization and the resulting thalamocortical processing are thought to underlie the observation that in many pain states the pain becomes widespread (Phillips and Clauw 2013). The significance of central sensitization in humans under clinically relevant conditions, and the experimental methods to test central sensitization in humans, will be addressed by Arendt-Nielsen (2015).

Ascending nociceptive information activates the thalamocortical system. During chronic pain states significant changes of this system were observed in patients using fMRI. Remarkably, many chronic pain states such as chronic osteoarthritic pain are associated with a so-called atrophy of the regions in which pain is processed. The underlying cellular mechanisms have not been identified. Interestingly, this atrophy seems to be reversible because after successful treatment of pain, the brain structures show a normalization (Bushnell et al. 2013; Gwilym et al. 2010; Rodriguez-Raecke et al. 2009). Under neuropathic conditions the cortex may show a reorganization with significant changes in the cortical maps. Such changes were, e.g., observed during phantom limb pain.

As already mentioned, ascending tracts not only activate the thalamocortical system. They also activate the amygdala via the parabrachial nucleus. Further input to the amygdala is provided by the nerve fibers from the thalamus and from the cortex (Duvarci and Pare 2014). The amygdala is key nuclei in the generation of fear, and they can be activated in pain conditions (Kulkarni et al. 2007). In this volume, the role of the amygdala and their connections to the medial prefrontal cortex (mPFC) in pain states will be addressed by Neugebauer (2015). Pain-related mPFC deactivation results in cognitive deficits and the failure of inhibitory control of amygdala processing. Impaired cortical control allows the uncontrolled persistence of amygdala pain mechanisms.

Neural pathways descending from the brain stem mediate inhibition and facilitation of nociceptive spinal cord neurons (Ossipov et al. 2010; Vanegas and Schaible 2004). During severe chronic pain, a reduction of descending inhibition, in particular the diffuse inhibitory noxious control (DNIC), was reported (Kosek and Ordeberg 2000; Lewis et al. 2012). In addition, descending facilitation may contribute to pain, in particular during neuropathic pain (Vanegas and Schaible 2004). Thus, descending inhibitory systems from the brain stem may be less effective and/or descending excitatory systems from the brain stem may be overactive during chronic pain. These changes may be (partly) reversible after successful pain treatment (Kosek and Ordeberg 2000).

Effects of the nervous system on inflammation. It must be noted that the importance of the nociceptive nervous system extends beyond the generation of pain. The nervous system is able to influence inflammatory processes in the organs. Such influences are mediated by the efferent effects of nociceptive sensory afferents which produce neurogenic inflammation, by fibers of the sympathetic and parasympathetic nervous system, and by neuroendocrine influences (Schaible and Straub 2014). Spinal hyperexcitability is not only important for pain generation (see above). It plays also a role in the regulation of joint inflammation (Waldburger and Firestein 2010). In this volume this topic will be addressed by Sorkin (2015). Both pro- and anti-inflammatory feedback loops can involve just the peripheral nerves and the spinal cord or can also include more complex, supraspinal structures such as the vagal nuclei and the hypothalamic–pituitary axis.