Peripheral system mechanism of pain modulation

The Pathophysiology of Pain

Peripheral system mechanisms of pain modulation

Peripheral nociceptors are an important target of pain therapy because many pathological conditions such as inflammation excite and sensitize peripheral nociceptors. Numerous ion channels and receptors for inflammatory mediators identified in nociceptors are involved in neuronal excitation and sensitization.1


Inflammation causes the release of numerous chemicals that may alter the sensitivity of peripheral nerve terminals. Chemical messengers that convey pain information to the central nervous system via the spinal cord can also affect the sensitivity of dorsal horn neurons. Glutamate is the predominant primary afferent neurotransmitter eliciting fast excitatory responses in post-synaptic neurons in the dorsal horn of the spinal cord. ATP enhances glutamate release during the firing of pre-synaptic autoreceptors and depolarization of post-synaptic dorsal horn receptors. Substance-P and calcitonin gene-related peptides promote vascular leakage and vasodilation, allowing circulating cells, plasma proteins and inflammatory mediators to infiltrate the infected area. Substance-P interacts with post-synaptic dorsal horn receptors, setting the magnitude of the nociceptive response. Bradykinin may play a critical role in inflammatory pain and hyperalgesia by acting directly on sensory nerves and by indirectly invoking the release of other inflammatory mediators from non-neuronal cells. Serotonin can intensify pain induced by bradykinin and enhance the response of nociceptors to bradykinin. Cytokines and corticotropin releasing hormone from inflamed tissue can induce macrophages, monocytes and lymphocytes to release endogenous opioids that mediate pain.2


Involvement of peripheral opioid receptors in analgesia

Opioid receptors are widely expressed in the central and peripheral nervous system and in the non-neuronal tissues. Peripheral opioid receptors have been shown to produce profound antinociception experimentally as well as clinically. Further receptors with inhibitory actions are receptors for somatostatin and cannabinoids. Experimentally, the use of specific agonists at these receptors produces antinociception.3


Data from animal and human clinical studies support the involvement of peripheral opioid receptors in analgesia, especially in the presence of inflammation. Inflammation has been shown to increase the synthesis of opioid receptors in the dorsal-root ganglion neurons and enhance transport and accumulation of opioid receptors in the peripheral terminals of sensory neurons. Under the influence of chemokines and adhesion molecules, opioid peptide-containing immune cells extravasate and accumulate in the injured tissues.4


Stress, chemokines, cytokines, and other releasing factors in inflamed tissues stimulate these granulocytes to release opioid peptides. Once secreted, opioid peptides bind to and activate peripheral opioid receptors on sensory nerve fibers and produce analgesia by decreasing the excitability of sensory nerves and/or inhibiting release of pro-inflammatory neuropeptides.5

1Schaible et al. Arthritis Research & Therapy 2011, 13:210.
2Wall and Melzack’s Textbook of Pain, 5th Edition pp16-17, 19, 35-36, 51. 2010
3Schaible et al. Arthritis Research & Therapy 2011, 13:210.
4Sehgal N. Pain Physician 2011; 14:249-258.
5Sehgal N. Pain Physician 2011; 14:249-258.