Nociception dorsal horn

Belcher, G., Ryall, R. W., and Schaffner, R. (1978) The differential effects of 5-hydroxytryptamine, noradrenaline and raphe stimulation on nociceptive and non-nociceptive dorsal horn intemeurons in the cat. Brain Res., 151 529-531. 

The locus cemleus is important for the regulation of attentional states and autonomic nervous system activity. It has also been implicated in the autonomic and stress-like effects of opiate withdrawal. A noradrenergic pathway originating from the locus cemleus which descends into the spinal cord is part of the descending inhibitory control system, which has an inhibitory effect on nociceptive transmission in the dorsal horn. 

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. 

The substantia gelatinosa is part of the dorsal horn of the spinal cord, also called lamina II . The substantia gelatinosa is made up almost exclusively of interneurons (both excitatory and inhibitory), some of which respond only to nociceptive inputs, while others respond also to non-noxious stimuli. 

Fig. 4.1 Hypothetical model of pathogenesis of pain in DSP. (1) Injury of peripheral nerve fibers due to multifocal inflammation and secreted macrophage activation products results in abnormal spontaneous activity of neighboring uninjured nociceptive fibers ( peripheral sensitization ). (2) Furthermore, the aberrant inflammatory response in DRG leads to alterations in neuronal sodium and calcium channel expression and ectopic impulse generation. (3) This results in central remodeling within the dorsal horn due to A-fiber sprouting and synaptic formation with pain fibers in lamina 11, and maintenance of neuropathic pain ( central sensitization ). Reproduced with permission from (Keswani et al. 2002)...

Lamina I forms the outer layer of the dorsal horn and contains the large marginal cells of Waldeyer and plays an important role in nociception since it is the layer in which... 

Two neurotransmitters are released by the nociceptive afferent fibers in the dorsal horn of the spinal cord. These neurotransmitters, which stimulate the... 

Stimulation of a nociceptor in the periphery of the body elicits action potentials in the first-order neuron, which transmits the signal to the second-order neuron in the dorsal horn of the spinal cord. From the spinal cord, the signal is transmitted to several regions of the brain. The most prominent ascending nociceptive pathway is the spinothalamic tract. Axons of the second-order sensory neurons project to the contralateral (opposite) side of the spinal cord and ascend in the white matter, terminating in the thalamus (see Figure 8.1). The thalamus contributes to the basic sensation or awareness of pain only it cannot determine the source of the painful stimulus. 

The dorsal horn is the first site of synaptic transfer in the nociceptive pathway 931... 

Spinal disinhibition allows more nociceptive signal input. Following peripheral nerve injury there is a reduction in the GABAergic component of postsynaptic inhibitory currents caused by a degeneration of GABAergic interneurons [24] (Fig. 57-6). This loss of inhibition (disinhibition) results in an overall increase in the excitability of dorsal horn neurons. The degeneration of inhibitory interneurons is due to an excitotoxic effect of primary afferent ectopic activity on dorsal horn neurons [26]. 

Neurotransmitters released by nociceptive afferents in the dorsal horn... 

Evidence from experimental pain research has revealed that mGluRs play a pivotal role in nociceptive processing, inflammatory pain and hyperalgesia. mGluRs have been implicated in dorsal horn neuronal nociceptive responses and pain associated with short-term inflammation (Neugebauer 2002) as well as its emotional component involving hmbic structures such as the amygdala (Han et al. 2004). 

The 5-HT3 receptor is the only monoamine neurotransmitter receptor that functions as a lig-and-gated ion channel, controlling the flux of Na-i- and K+ ions. 5-HT3 receptors are located on parasympathetic nerve terminals in the gastrointestinal tract, and high densities are found in areas of the brain associated with the emetic response, such as the area postrema. The antiemetic effects of 5-HT3 antagonists, such as ondansetron, result from actions at these sites. 5-HT3 receptors in the dorsal horn of the spinal cord have been implicated in nociception and development of new 5-HT3 receptor-related compounds may have potential as non-opioid, non-addictive analgesics. 

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to (kappa) opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it may play a critical role in the sensitization of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor. Moreover, dynorphin A can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development. 

The central nervous system (CNS) - the brain and spinal cord - is involved in the reception and interpretation of peripheral afferent nociceptive impulses. Reflexes mediated by spinal interneurons and the gating functions of the dorsal horn of the spinal cord are particularly crucial. However, our knowledge of brain mechanisms is still limited. 

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