Komplett gjennomgang av alle mulige mekanismer bak smerte, spesielt relatert til senesmerter.

Nevner noe svært spennende og at senesmerter, feks i achilles, kan være mer pga beskyttelse enn pga betennelse eller nocicepsjon. Derfor blir det vondt ved mer bevegelse. Hjernen prøver å beskytte kroppen mot for hard bevegelse, men feilberegner intensiteten og skaper smerte før det er nødvendig.

http://www.ncbi.nlm.nih.gov/pubmed/24027089

Finnes i sin helhet på BodyInMind sin hjemmeside.

Clinicians and researchers distinguish between physiolog- ical and pathophysiological pain. Physiological or ‘noci- ceptive’ pain is considered to reflect activation of primary nociceptors following actual or impending tissue damage or in association with inflammation. This type of pain is a helpful warning sign and is considered to be of evolu- tionary importance. Pathophysiological pain is associated with functional changes within the nervous system, such as ectopic generation of action potentials, facilitation of syn- aptic transmission, loss of synaptic connectivity, formation of new synaptic circuits, and neuroimmune interactions as well as cortical topographical changes [17], making it resistant to tissue-based treatments and it appears to pro- vide no evolutionary advantage or helpful warning.

Modern under- standing of pain suggests that nociception is neither suffi- cient nor necessary for pain [27]. Nociception refers to activity in primary afferent nociceptors—unmyelinated C fibres and thinly myelinated Ad fibres—and their projec- tions to the cortex via the lateral spinothalamic tract (Fig. 1). The projections terminate in multiple regions but predominantly the thalamus, which transmits impulses to the somatosensory cortex.

Pain, on the other hand, is an emergent property of the brain of the person in pain [28]. A useful conceptualisation is that pain emerges into consciousness in association with an individually specific pattern of activity across cortical and subcortical brain cells [29].

The relationship between nociception and pain becomes more tenuous as pain persists, and research has uncovered profound changes in the response profile of neurons within the nociceptive neuraxis.

Allodynia and primary hyperalgesia are attributed to sen- sitisation of the primary nociceptor and relate to the area of usual pain. In tendinopathy, if normally pain-free move- ments, for example jumping, evoke tendon pain, this can be termed allodynia. If palpation of the Achilles tendon evokes more pain than usual, this can be termed primary hyperalgesia.

Secondary hyperalgesia and allodynia are attributed to sensitisation of nociceptive neurons within the central nervous system (CNS), collectively called central sensiti- sation, and relate clinically to areas away from the primary ‘zone’. Tenderness and evoked pain that spread, in a non- dermatomal, non-peripheral nerve distribution is best explained by central sensitisation [36].

Glial cells, not yet investigated in tendon but evident in other connective tissues [51], share a bone marrow lineage [52] and an immune role. Glial cells, which are capable of neurotransmission in chronic injury [53], communicate information between the peripheral nervous system (PNS) and CNS [54, 55] and when activated are implicated in ongoing pain [56] and may be another cell type potentially involved in tendon pain.

Autonomic nerves, particularly sympathetic nerve endings in blood vessel walls [65], have been reported in the tendon, peritendon and endotendon of the patellar tendon [66, 67]. Sensory and sympathetic perivascular innervation of the walls of large and small blood vessels occur in peritendinous loose connective tis- sue, and there are some sensory nerve endings in the superficial endotendon [61].

Neuropeptides such as SP and calcitonin gene-related peptide (CGRP) transmit signals across a synapse. Both SP and CGRP are released by the terminals of nociceptors and SP has been shown to be released by tenocytes. SP afferent immunoreactivity has been demonstrated at the enthesis [106] and in tendon tissue [61, 64], which indicates thin fibre sensory innervation, most likely serving a nociceptive function. SP [and its receptor, neurokinin-1 receptor (NK-1 R)] and CGRP have also been identified in nerve fascicles in large and small blood vessels in tendinopathy [107]. Binding of SP to its receptor has been associated with the transmission of nociception [108].

SP can cause vasodilation and protein extravasation in surrounding tissue—a process termed neurogenic or pep- tidergic inflammation. SP increases cell metabolism, cell viability and cell proliferation in tenocytes [109]. The peptidergic inflammatory mechanism of nociceptors is initiated by nociceptor activation. However, antidromic mechanisms driven within the CNS can lead to peptidergic inflammation and this raises the possibility that central mechanisms influence tendon pain.

All cells and tissues require the maintenance of intracel- lular and tissue pH, as many processes and proteins only function within specific pH ranges [44]. Cell membrane potential, which is the difference in voltage between the inside and outside of the cell, determines the excitability of the cell and is influenced by tissue pH. Lactate can decrease pH, and microdialysis of tendinopathic tissue showed lactate levels at rest were double that shown in healthy control tendon [121]. Increased lactate, due to a predominant anaerobic metabolism, occurs in tendons of older people as well as tendinopathy [122, 123], and is compounded by the high metabolic rate in tendon pathol- ogy (25 times that of normal tendon) [124].

At physiological pH, lactic acid almost completely dis- sociates to lactate and hydrogen ions; the latter are known to modulate nociceptor activity and alter ion channel expression.

Lactate can stimulate collagen production and deposition, activate tenocytes [125] and increase vascular endothelial growth factor (VEGF) and neovascularisation [126]. Lactate also closes the inhibitory gap junctions between rows of tenocytes, which may exaggerate response to loading [127].

Accumulated lactate has been associated with pain in other tissues such as cardiac and skeletal muscle and the intervertebral disc (IVD), but it has not been fully inves- tigated for tendons. It is notable that tendon pain has some features that are consistent with accumulated lactate: rapid easing in symptoms after a change of posture (sustained positions are painful in tendinopathy), poor response to anti-inflammatory medication (true in tendons for most anti-inflammatory medications, those that alter pain and function appear to do so by tenocyte down-regulation and PG inhibition [128, 129] and sometimes no evidence of clear pathology [76].

Ion channels, present in cell membranes, alter the flow of ions in and out of a cell and respond to voltage, movement or chemicals. Ion channels in tenocytes may perform a number of roles, including mediation of calcium signalling, osmoregulation and cell volume control, control of resting membrane potential levels and the detection of mechanical stimuli [130]. Ion channels are important in tendon pain; they may be involved in sensing the nociceptive stimuli, communicating with the afferent nerves and neuronal transmission to and within the cortex.

Ion channel expression is likely to change in tendinopathy because of a more acidic environment due to excess lactate. A decrease of the extracellular pH influences the expression of acid- sensing ion channels (ASICs) [131]. The magnitude of currents in ASICs is sufficient to initiate action potentials in neurons [131]; ASICs are activated quickly by hydrogen ions and inactivate rapidly despite continued presence of low pH, exhibiting features of saturation.

ASICs have been associated with painful conditions that have accompanying tissue acidosis and ischaemia, and they were therefore originally thought to only be expressed by neurons.

Ion channel expression in tenocytes may change, but ion channel expression in the afferent nerve may also change in response to repeated activation [36]. This sensitises the primary neuron to the very stimulus that evoked the adjustment.

Ion channels are normally closed in the absence of a stimulus, but open for a few milliseconds to allow equal- isation along an electrical gradient [153]. With prolonged (chemical or electrical) stimulation, many of these chan- nels close and desensitise, leaving them refractory to fur- ther opening unless the stimulus is removed.

Although ASICs have not been studied in normal, pathological or painful tendons, the tendon environment can become acidic [121] to levels that would open ASIC channels if they were expressed by tenocytes or neurons.

Desensitisation occurs with persistent stimulation of ASICs after approximately 3 min [154], which may explain the clinical feature of tendons being initially painful during activity then warming up. Recovery from desensitisation occurs slowly, over many hours, which may fit with later pain and stiffness. ASICs are rapidly activating and inac- tivating (\5 ms to activate, 400 ms to deactivate) [155] which may also fit with the on/off nature of tendon pain. Further investigation of the presence and role of ion channels in tendon pain is warranted.

There may be non-nociceptive mechanisms that play a noci- ceptive role in tendon pain. One such mechanism may be related to an internal calculation of tendon load. This idea is consistent with the modern idea of pain being about protection and not dependent on nociception, and shares characteristics with the central governor theory of fatigue [188].