Disease relevance of Nociceptors

• However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity [1].
• Noradrenaline hyperalgesia is mediated through interaction with sympathetic postganglionic neurone terminals rather than activation of primary afferent nociceptors [2].
• There is evidence that substance P is a peptide neurotransmitter of some unmyelinated primary afferent nociceptors and that its release from the peripheral terminals of primary afferent fibers mediates neurogenic inflammation [3].
• Indirect actions of bradykinin on neonatal rat dorsal root ganglion neurones: a role for non-neuronal cells as nociceptors [4].
• In this case a drop in pH may accompany the ischemia and BKN are known to be effective stimulants for muscle nociceptors [5].

Psychiatry related information on Nociceptors

• Pain thresholds in normal skin were matched only by the response thresholds of CMH and not AMH nociceptors [6].

High impact information on Nociceptors

• Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chemical and thermal stimuli [7].
• Inflammation causes the induction of cyclooxygenase-2 (Cox-2), leading to the release of prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity [8].
• The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels [9].
• Nociceptors had currents that were similar to those of heterologously expressed channels containing P2X3 subunits, and had P2X3 immunoreactivity in their sensory endings and cell bodies [10].
• NMDA-receptor regulation of substance P release from primary afferent nociceptors [11].

Chemical compound and disease context of Nociceptors

• These capsaicin-insensitive A-fibre nociceptors may also mediate hyperalgesia in neuropathic pain [12].
• The co-treatment of the animals with IL-8 plus atenolol, but not with indomethacin, prevented the induction of persistent mechanical nociceptor hypersensitivity [13].
• We conclude that systemic lidocaine reduces pin-prick hyperalgesia by a central mode of action, which could involve blockade of terminal branches of nociceptors [14].
• Retention of MOR expression and activity in nearby non-injured afferents will enable, however, an opioid-mediated reduction of stimulus-evoked and spontaneous pain carried by intact nociceptor afferents and we find that intrathecal DAMGO (1000 ng) reduces mechanical hypersensitivity in rats with SNL [15].
• We conclude that silver nitrate cauterization produces acute corneal inflammation and hyperalgesia, and may prove a useful model for the study of primary afferent nociceptors [16].

Biological context of Nociceptors

• We show here that Runx1, a Runt domain transcription factor, is expressed in most nociceptors during embryonic development but in adult mice, becomes restricted to nociceptors marked by expression of the neurotrophin receptor Ret [17].
• In addition, TNF evoked ongoing activity in 14% of C nociceptors and caused significant and dose-related increases in vascular permeability in glabrous skin [18].
• Thus, peripheral NMDA receptors not only play an important role in modulating the responses of nociceptors in normal skin, but their upregulation and activation on peripheral nociceptors contributes significantly to the mechanical sensitivity and heat sensitization that accompanies persistent inflammation [19].
• Primary afferent nociceptors contain and release neuropeptides including calcitonin gene-related peptide, implicated in inflammatory vasodilatation [20].
• Higher concentrations of muscimol further depolarize GABA(A) receptor-containing terminals, which then initiates action potentials in nociceptors analogous to the appearance of dorsal root reflexes that arise following activation of GABA(A) receptors on central primary afferent terminals [21].

Anatomical context of Nociceptors

• After nerve damage but not in its absence, sympathetic stimulation and norepinephrine were excitatory for a subset of skin C-fiber nociceptors and enhanced the responsiveness of these nociceptors to tissue-damaging stimulation [22].
• Loss of DRASIC increased the sensitivity of mechanoreceptors detecting light touch, but it reduced the sensitivity of a mechanoreceptor responding to noxious pinch and decreased the response of acid- and noxious heat-sensitive nociceptors [23].
• Thus, our results support the suggestion that glutamate release in the spinal cord during inflammation causes retrograde hypernociception of nociceptors associated with sodium tetrodotoxin-resistant channels in primary nociceptive sensory neurons [24].
• The same stimuli were delivered to the receptive fields of C fiber and A fiber mechanoheat-sensitive nociceptors (CMH and AMH nociceptors, respectively) and of low threshold warm and cold receptors in the anesthetized monkey and to the receptive fields of CMH nociceptors recorded percutaneously from the peroneal nerve of awake humans [6].
• NPY receptors are therefore uniquely positioned to inhibit primary afferent nociceptors directly, especially after peripheral nerve injury [25].

Associations of Nociceptors with chemical compounds

• Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1 [26].
• We conclude that PKC-epsilon is principally responsible for sensitization of the heat response in nociceptors by bradykinin [27].
• It is proposed that glutamate is the neurotransmitter in primary afferents mediating input from different peripheral receptor classes, including nociceptors [28].
• Activation of presynaptic NMDA receptors coupled to NaV1.8-resistant sodium channel C-fibers causes retrograde mechanical nociceptor sensitization [24].
• The final step in the direct restoration of the nociceptor threshold by peripheral administration of morphine and dipyrone was recently suggested to result from the opening of ATP-sensitive K(+) channels (K(ATP)(+)) [29].

Gene context of Nociceptors

• Our results suggest that ASICs are leading acid sensors in human nociceptors and that VR1 participates in the nociception mainly under extremely acidic conditions [30].
• Brain-derived neurotrophic factor (BDNF) might be released by nociceptors onto spinal neurons and mediate central sensitization associated with chronic pain [31].
• Together, these findings suggest that BDNF may be released from primary sensory nociceptors with activity, particularly in some persistent pain states, and may then increase the excitability of rostrally projecting second-order systems [32].
• Using whole-cell patch-clamp recordings, we show that the B1 receptor was not necessary for regulating the noxious heat sensitivity of isolated nociceptors [33].
• Somatostatin receptors on peripheral primary afferent terminals: inhibition of sensitized nociceptors [34].

Analytical, diagnostic and therapeutic context of Nociceptors

• 7. It is concluded that activity in C mechanoheat (polymodal) nociceptors contributes to the magnitude and duration of pain evoked by intradermal injection of capsaicin [35].
• In sound stressed animals, bradykinin-hyperalgesia had a more rapid latency to onset and was no longer inhibited by sympathectomy, compatible with a direct effect of bradykinin on primary afferent nociceptors [36].
• Furthermore, demonstration of glutamate-induced excitation and heat sensitization of nociceptors indicates that local or topical administration of glutamate receptor antagonists may have therapeutic potential for the treatment of pain [37].
• These results suggest that selective acute tolerance of peripheral morphine analgesia, but not U-69593 analgesia, through MORs and KORs located on polymodal nociceptors, respectively, in the bradykinin-nociception test in mice was mediated through protein kinase C activation [38].
• In barbiturate-anesthetized male rats, corneal nociceptors were excited by pulses of CO2 gas, and GABAA receptors were activated by microinjections of the selective agonist muscimol [39].

References