Nociceptors sensitization

Aspirin, non-acetylated salicylates, and other NSAIDs have analgesic, antipyretic, and anti-inflammatory actions. These agents inhibit cyclooxygenase (COX-1 and COX-2) enzymes, thereby preventing prostaglandin synthesis, which results in reduced nociceptor sensitization and an increased pain threshold. NSAIDs are the preferred agents for mild to moderate pain in situations that are mediated by prostaglandins (e.g., rheumatoid... 

Duarte IDG, Dos Santos IR, Lorenzetti BB, Ferreira SH (1992) Analgesia by direct antagonism of nociceptor sensitization involves the arginine-nitric oxide-cGMP pathway. Eur 1 Pharmacol 217 225-227... 

The recognition and control of nociceptor transduction and development of primary hyperalgesia are key to reducing the intensity and duration of acute pain. Nociceptor sensitization leads to reductions in noxious thresholds, increased pain disability, and delayed rehabilitation. The physiological response to transduction and the initiation of nociception can be limited or eliminated by peri operative administration of non-opioid analgesics and anti-inflammatory agents (e.g. NS AIDS, steroids). Although opioids can inhibit... 

It is widely assumed that tramnatic injiuy to the nerve is the major cause of post-operative neiu-opathlc pain, but it is probably more complicated than this suggestion. It is also likely that the particular procedure and sensory systems in the surgical field contribute. Additionally, in some patients, continuous inflammatory responses, such as after inguinal hernia repair, drive the chronic response. However, it is the role of peripheral nociceptor sensitization that seems to be at the center of this issue. 

Antiepileptics are used in neuropathic pain resulting from lesions to the peripheral (e.g., diabetes, heipes) or central nervous system (e.g., stroke). Such syndromes have been attributed to ectopic activity in sensitized nociceptors from regenerating nerve sprouts, recruitment of previously silent nociceptors, and/or spontaneous neuronal activity. This may result in sensitization... 

Table 8.1 Endogenous Chemicals Activating or Sensitizing Nociceptors... 

An injured area is typically more sensitive to subsequent stimuli. As a result, painful stimuli, or even normally nonpainful stimuli, may cause an excessive pain response. An increase in the sensitivity of nociceptors is referred to as primary hyperalgesia. A classic example of hyperalgesia is a bum. Even light touch of a burned area may be painful. 

Nonnarcotic analgesics. The nonnarcotic analgesics include aspirin, NSAIDs, and acetaminophen. Aspirin acts centrally and peripherally to block the transmission of pain impulses. Furthermore, it reduces fever and inflammation and inhibits synthesis of the prostaglandins that increase the sensitivity of nociceptors. 

Inflammatory pain results from changes both in primary sensory and dorsal horn neurons 933 Peripheral sensitization lowers nociceptor activation threshold 933... 

Inflammatory pain results from changes both in primary sensory and dorsal horn neurons. The alterations in primary sensory neurons fall into two broad categories (a) a reduction in threshold and an increase in the response of the peripheral terminals of nociceptors (peripheral sensitization), and (b) an alteration in transmitter content modifying synaptic input to the spinal cord. In the dorsal horn, peripheral inflammation results in an increase in membrane excitability and synaptic efficacy, which is the phenomenon of central sensitization [12]. 

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. 

Nociceptors. PG increase sensitivity of sensory nerve fibers towards ordinary pain stimuli (p. 194), i.e., at a given stimulus strength there is an increased rate of evoked action potentials. 

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). 

Unlike most receptors, nociceptors can become increasingly sensitive after injury (i.e. when the stimulus is very strong) or when the stimulus is continuing or repeated. This sensitization means that there can be a reduction in the threshold for activation (i.e. pain signals will be transmitted in response to even gentle stimuli), an increase in the response to a given stimulus, or even the appearance of spontaneous activity. 

The basis for the analgesic action of NSAIDs is their ability to prevent the production of prostaglandins. Prostaglandins are derived from the arachidonic acid cascade and are implicated in the production of inflammatory pain and in sensitizing nociceptors to the actions of other mediators. 

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... 

Ziegler, E. A., Magerl, W., Meyer, R. A., and Treede, R. D. (1999). Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. Brain 122(Pt 12), 2245-2257. 

Nelson MT, Woo J, Kang H-W et al. (2007) Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels. J Neurosci 27(31) 8250-8260... 

Lowering of the sensitivity of nociceptors (antipyretic analgesics, local anesthetics)... 

COX-2 is induced by inflammatory processes and produces prostaglandins that sensitize nociceptors, evoke fever, and promote inflammation by causing vasodilation and an increase in vascular permeability. However, in some organs, COX-2 is also expressed con-stitutively (kidney, vascular endothelium, uterus, and CNS). 

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