Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

/pdf/central-sensitization-implications-for-the-diagnosis-and-18p4x3px9q.pdf

Central sensitization: implications for the diagnosis and treatment of pain.

http://www.columbia.edu/cu/biology/courses/w3004/recitation7.pdf

The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli

The cellular and molecular mechanisms that enable us to sense cold are not well understood. Insights into this process have come from the use of pharmacological agents, such as menthol, that elicit a cooling sensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that it functions as a transducer of cold stimuli in the somatosensory system. These findings, together with our previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.

Identification of a cold receptor reveals a general role for TRP channels in thermosensation

Repetitive stimulation of small diameter primary afferent fibres produces a progressive increase in action potential discharge (windup) and a prolonged increase in the excitability of neurones in the spinal cord following the stimulus. Previous studies have demonstrated that windup is the consequence of the temporal summation of slow synaptic potentials and that the slow potentials and windup are reduced by pretreatment with N-methyl-D-aspartic acid (NMDA) antagonists. We have now examined whether primary afferent induced hypersensitivity states in flexor motoneurones are also dependent on the activation of NMDA receptors and whether windup is a possible trigger for the production of the central hypersensitivity. Both a non-competitive (MK-801) and a competitive (D-CPP) NMDA antagonist, at doses that did not modify the baseline reflex, reduced the facilitation of the flexor reflex produced by either brief electrical stimulation of the sural nerve (1 Hz for 20 sec at C-fibre strength), or by the cutaneous application of the chemical irritant mustard oil. These antagonists also prevented windup from occurring in the motoneurones. When the the MK-801 and the D-CPP were administered once a state of central facilitation had been induced by prior treatment with mustard oil, they returned the facilitated reflex to its pretreatment level. These results indicate that NMDA receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs. Because central sensitization is likely to contribute to the post-injury pain hypersensitivity states in man, these data have a bearing both on the potential role of NMDA antagonists for pre-emptive analgesia and for treating established pain states.

The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states.

http://yael-nissan.weebly.com/uploads/5/2/9/2/5292348/the_introduction_to_pain_an_integrative_review_-_millan.pdf

The induction of pain: an integrative review

the concept that sense organs of the skin with unmyelinated (C) fibers have widely varying functional characteristics. In the mammal, a large proportion of such sensory units are excited by gentle mechanical stimuli (8, 16, 34) and by transient cooling (9). Others are described as responding best to small temperature changes (13, 18) and some are reported to have elevated thresholds for various or all stimuli (14, 15, 18, 32). Studies proposing large and important differences between various afferent units with C fibers have drawn conclusions from a small or highly selected population and no view has been provided of the way in which these differences fit into the spectrum presented by the sensory structures from a given skin region. Such information seems essential for the understanding of somatic sensation inasmuch as unmyelinated fibers far outnumber myelinated fibers in the afferent nerves from the skin. In particular, unmyelinated afferent fibers are generally agreed to have some causal relation to pain and its associated reactions (3, 6, 7, 25). A crucial issue in hypotheses correlating afferent activity to pain is whether the underlying mechanisms are set off by impulses from sensory structures responding only to noxious stimuli (i.e., intense enough to threaten or (cause tissue damage) or whether they are triggered by special patterns of discharge from nonspecific afferent units (25). In an attempt to learn more about the range of behavior associated with the terminals of cutaneous C fibers, we surveyed a number of randomly sele,cted units for responses to a variety of graded stimuli. The results point out that a large proportion of

P Bessou

Papers

Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli.