Activation Of Nociceptive Afferent Fibers Research Articles

Human models of hyperalgesia and pain (chilli pepper with your acid indigestion, Sir?)

The perception of harmful stimuli (termed nociception from Sherrington’s terms ‘nociceptive’ and ‘nociceptor’) is closely related to, but distinct from, the sensation of pain. Polymodal nociceptors (PMNs) are peripheral sensory neurons that respond to noxious (i.e. potentially tissuedamaging) stimuli. They are mainly non-myelinated C fibres whose endings respond to intense thermal, mechanical and chemical stimuli (and hence are ‘polymodal’). PMN fibres terminate in the dorsal horn of the spinal cord, forming synaptic connections with transmission neurons running to the thalamus. Chemical stimuli acting on PMNs include bradykinin, protons, ATP and vanilloids (e.g. capsaicin, the component of chilli peppers responsible for their fiery flavour). PMNs are sensitized by prostaglandins, which explains the analgesic effect of antiinflammatory drugs, particularly in the presence of inflammation. The transient receptor potential vanilloid receptor 1 (TRPV1) receptor responds to noxious heat as well as capsaicin-like agonists. Pain (distinct from nociception) includes a strong emotional component; its intensity depends critically on several additional factors in conjunction with the noxious stimulus itself, notably the context in which tissue injury occurs (e.g. football pitch vs. dentist’s chair), its chronicity and any associated inflammation. All of these strongly influence the threshold at which a potentially harmful stimulus is perceived as painful.Reduction in this threshold defines the state of hyperalgesia (enhanced pain from even a mildly noxious stimulus), familiar to anyone who has suffered a sprained ankle or a scald, and which results from a combination of sensitization of peripheral nociceptive nerve terminals and facilitation of central pain pathways. Peripheral sensitization is due to mediators such as bradykinin and prostaglandins, while the central component reflects facilitation of synaptic transmission in the central pain pathways [1]. Central facilitation displays the phenomenon of ‘wind-up’ (synaptic potentials steadily increase in amplitude with each stimulus) and is prevented by antagonists of NMDA, and of substance P and by inhibitors of nitric oxide synthesis, although none of these antagonists or inhibitors has as yet led to new and therapeutically useful analgesic drugs. Substance P and calcitonin gene-related peptide (CGRP), released from the central connections of C-fibres in the dorsal horn of the spinal cord, are also released peripherally (as a consequence of an axon reflex), causing neurogenic inflammation, which amplifies and sustains the activation of nociceptive afferent fibres. Nerve growth factor (NGF), a cytokine-like mediator produced by inflamed tissue, acts on a kinaselinked receptor known as TrkA located on PMNs, and increased production of NGF may cause hyperalgesia [2]. Many analgesics, particularly opioids, disproportionately reduce the distress associated with pain compared with their effect on awareness of the noxious stimulus per se, and this is not explained by nonspecific sedative effects. The activity of opioid analgesics in animal models such as the mouse ‘tail-flick’ (a flick of the tail in response to heat), which mainly assess antinociceptive activity, is poorly correlated with clinical efficacy [1]. Can tests in humans do better? Symptoms of pain in diseases such as myocardial infarction, arthritis or pancreatitis are dramatically Sherrington also introduced the term ‘synapse’. British Journal of Clinical Pharmacology DOI:10.1111/j.1365-2125.2010.03725.x

Endomorphin-2 is not released from rat spinal dorsal horn in response to intraplantar formalin

Antibody coated microprobes, inserted into the spinal cord at the L4–5 level, were used to detect whether endomorphin-2 (Endo2) was released from spinal dorsal horns in anesthetized rats in response to formalin injected into the hindpaw footpads. Saline injections were used as a control and substance P (SP) was measured to verify activation of nociceptive afferent fibers. SP but not Endo2 was released during pre-stimulation periods. Saline injections did not cause the release of either Endo2 or SP from the spinal cord. Formalin injections caused an increase in Fos expression as well as a release of SP, but not Endo2 from the ipsilateral side dorsal horn in L4–5. We conclude that Endo2 does not play a role in mediating the in vivo responses to acute inflammatory nociceptive signals at the spinal level in the anesthetized rat model.

Selective antagonism of capsaicin by capsazepine: evidence for a spinal receptor site in capsaicin‐induced antinociception

1. Capsazepine has recently been described as a competitive capsaicin antagonist. We have used this compound to test the hypotheses that the in vitro and in vivo effects of capsaicin are due to interactions with a specific receptor. 2. In an in vitro preparation of the neonatal rat spinal cord with functionally connected tail, the activation of nociceptive afferent fibres by the application of capsaicin, bradykinin or noxious heat (48 degrees C) to the tail could be measured by recording a depolarizing response from a spinal ventral root. Application of capsaicin or substance P to the spinal cord also evoked a depolarizing response which was recorded in a ventral root. 3. When capsazepine (50 nM-20 microM) was administered to the tail or spinal cord it did not evoke any measurable response. However on the tail, capsazepine reversibly antagonized (IC50 = 254 +/- 28 nM) the responses to capsaicin but not to heat or bradykinin administered to the same site. Similarly capsazepine administration to the spinal cord antagonized the responses evoked by capsaicin (IC50 = 230 +/- 20 nM) applied to the cord but not responses evoked by substance P on the cord or by noxious heat and capsaicin on the tail. 4. In halothane anaesthetized rats, C-fibre responses evoked by transcutaneous electrical stimulation of the receptive field were recorded from single wide dynamic range neurones located in the spinal dorsal horn. C-fibre evoked discharges were consistently reduced by the systemic administration of capsaicin (20 mumol kg-1, s.c.) and this action of capsaicin was antagonized by capsazepine (100 mumol kg-1) administered by the same route. In addition the systemic effect of capsaicin was antagonized by a spinal intrathecal administration of capsazepine (5-50 nmol). 5. Intradermal injections of capsaicin, localized to the peripheral receptive field, usually one toe of the ipsilateral hind-paw, produced a transient increase in C-fibre-evoked activity followed by a prolonged period of localized insensitivity to transcutaneous C-fibre stimulation. These effects of capsaicin were significantly reduced by the concommitant administration of capsazepine to the same site. 6. These data demonstrate that capsazepine is a selective antagonist of capsaicin on nociceptive neurones in vitro and in vivo and suggest that the effects of capsaicin were mediated by activation of a specific receptor. Since the antinociceptive effect produced by systemically administered capsaicin was antagonised by spinal intrathecal capsazepine this further supports the hypothesis that capsaicin exerts its antinociceptive effect by acting on specific receptors localized to sensory nerve fibres in the spinal cord.