Nociceptors mechanical

Thermal nociceptors and mechanical nociceptors are associated with A-delta fibers. These are small myelinated fibers that transmit impulses at a rate of 5 to 30 m/sec. Polymodal nociceptors are associated with C fibers. These are small unmyelinated fibers that transmit impulses at a rate generally less than 1.0 m/sec (range of 0.5 to 2.0 m/sec). 

Muscle spasm. The pain induced by muscle spasm results partially from the direct effect of tissue distortion on mechanical nociceptors. Muscle spasm also causes tissue ischemia. The increased muscle tension compresses blood vessels and decreases blood flow. Furthermore, the increased rate of metabolism associated with the spasm exacerbates the ischemia. As discussed earlier, ischemia leads to stimulation of polymodal nociceptors. 

Stein C, Gramsch C, Herz A (1990) Intrinsic mechanisms of antinociception in inflammation local opioid receptors and beta-endorphin. J Neurosci 10 1292-1298 Steiner AA, Branco LGS, Cunha FQ, Ferreira SH (2001) Role of the haeme oxyge-nase/carbon monoxide pathway in mechanical nociceptor hypersensitivity. Br J Pharmacol 132 1673-1682... 

Sachs D, Cunha F Q, Poole S, et al. (2002). Tumour necrosis factor-alpha, interleukin-Ibeta and interleukin-8 induce persistent mechanical nociceptor hypersensitivity. Pain. 96 89-97. 

The pain appears to arise from the formation of melittin pores in the membranes of nociceptors, free nerve endings that detect harmful ( noxious —thus the name) stimuli of violent mechanical stress, high temperatures, and irritant chemicals. The creation of pores by melittin depends on the nociceptor membrane potential. Melittin in water solution is tetrameric. However, melittin interacting with membranes in the absence of a membrane potential is monomeric and shows no evidence of oligomer... 

Nociceptors are a specific subset of peripheral sensory organs, which respond to noxious stimuli. A8 mechan-oreceptors and C-polymodal nociceptors are the two main classes of cutaneous nociceptors. The sensory quality of pain evoked by activation of A8-fibres is... 

Afferent input from cutaneous and visceral nociceptors is known to converge on spinal neurons, which accounts for the referral of pain between visceral and cutaneous structures (e.g. cardiac pain gets referred to the chest and left upper arm in patients suffering from angina pectoris). Projection neurons in the spinal dorsal horn project to cell nuclei in supraspinal areas such as the thalamus, brainstem and midbrain. Of these, the synaptic junctions in the thalamus play a very important role in the integration and modulation of spinal nociceptive and non-nociceptive inputs. Nociceptive inputs are finally conducted to the cortex where the sensation of pain is perceived (Fig. 1). The mechanisms via which the cortex processes nociceptive inputs are only poorly understood. 

Hydrogen ions accumulate in tissue damaged by inflammation and ischaemia and so pH is lowered. These protons may activate nociceptors directly via their own family of ion channels as well as sensitising them to mechanical stimulation. Acid-sensing ion channels (ASICS) are a family of sodium channels that are activated by protons — of special interest is one type found only in small dorsal root ganglion neurons that possibly are responsible for activation of nociceptors. Although the transduction of mechanical stimuli is poorly understood, ASICs are closely related to channels that respond to stretch. 

Nociceptors Receptors for pain caused by injury from physical stimuli (mechanical, electrical, or thermal) or chemical stimuli (toxins). Nociceptors are located in the skin, muscles, and in the walls of the viscera. 

Primary sensory neurons sense pain and convey it to the spinal cord. Nociceptors have unmyelinated (C fiber) or thinly myelinated (AS) axons, while the low-threshold Ap-fiber mechanoreceptors involved in tactile and proprioceptive perception have large myelinated sensory neurons (Table 57-1). The peripheral terminals of primary sensory neurons convert changes in the environment into neuronal activity by transducing mechanical (Ch. 51), thermal or chemical stimuli into ion fluxes across their... 

FIGURE 57-2 Noxious chemical, thermal and mechanical stimuli activate specific high-threshold receptors and ion channels that lead to inward currents in the peripheral terminals of nociceptors. 

Pain is thought to originate from myofascial factors and peripheral sensitization of nociceptors. Central mechanisms are also involved. Mental stress, nonphysiologic motor stress, a local myofascial release of irritants, or a combination of these may be the initiating stimulus. In predisposed individuals, chronic, tension-type headache can evolve. 

Stimulation of free nerve endings known as nociceptors is the first step leading to the sensation of pain. These receptors are found in both somatic and visceral structures and are activated by mechanical, thermal, and chemical factors. Release of bradykinins, K1, prostaglandins, histamine, leukotrienes, serotonin, and substance P may sensitize and/or activate nociceptors. Receptor activation leads to action potentials that are transmitted along afferent nerve fibers to the spinal cord. 

V.c.1.1. Cyclo-oxygenase inhibition. Inhibition of cyclo-oxygenase reduces the level of circulating prostaglandins and neurogenic inflammation. This is the mechanism of action of nonsteroidal antiinflammatory drugs (NSAID) and aspirin. The mode of action of paracetamol is less clear (inhibition of prostaglandins in the nociceptors of the posterior horn of the spinal cord and action on the supraspinal structures implicated in nociception). 

Despite intensive research on the neurobiological mechanisms of chronic pain, this therapeutic area remains one of the least satisfactorily covered by current drugs. There is considerable preclinical evidence that hyperalgesia and allody-nia following peripheral tissue or nerve injury is not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depends on NMDA receptor-mediated central changes in synaptic excitabihty (Zieglgansberger and Tolle 1993 Sandkiihler and Liu 1998 Hide 2000 Parsons 2001 Fundytus 2001). 

An electrophysiological study has shown that muscarine treatment of C-units left them with a marked and sustained desensitization to mechanical and heat stimuli (Bernadini et al., 2001). The mechanical desensitization is in agreement with preceeding results where the ACh analog carbachol was shown to excite C-nociceptors and at the same time produced desensitization to mechanical stimulation lasting up to 45 minutes (Steen and Reeh, 1993). 

Activation of nociceptor PKRs by Bv8 in rats and mice produces nociceptive sensitization to thermal and mechanical stimuli, without inducing any spontaneous, overt nocifensive behavior, or local inflammation. Very low doses of Bv8 (50 fmol) injected into the paw induce a decrease in the nociceptive threshold that reaches the maximum in 1 h and disappears in 2-3 h. The same dose i.th., or higher doses by systemic routes (s.c. and i.v.), induces hyperalgesia with a characteristic biphasic time-course the first peak occurs in 1 h and the second peak invariably in 4—5 h. The first phase depends on a direct action on nociceptors, because it resembles that... 

---