8. Pain Modulation and Mechanisms
Part 2 of 3

Nachum Dafny, Ph.D.
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Neuronal Circuits that Modulate Pain (continued)

Stimulation produced analgesia (SPA) (continued)

To verify whether the electrical stimulation produced analgesia via the release of opiate and serotonin, the area was locally microinjected with morphine or 5-HT. These microinjections indeed produce analgesia (Figure 8.3). These procedures also provide a method of identifying brain regions associated with pain suppression and help to produce a map of pain centers. The most effective method of producing opiate analgesia (OA) is by intracerebral injection of morphine into the PAG.

The PAG and RN and other brain structures where analgesia is produced are also rich in opiate receptors. Intracerebral opioid administration produced analgesia and SPA can be blocked by either systemic or by local microinjections of naloxone, the morphine antagonist, into the PAG or RN. Therefore, it has been suggested that the two (OA and SPA) operate by a common mechanism.

If OA and SPA act through the same intrinsic system, then the hypothesis that opiates activate a pain-suppression mechanism is more likely. In fact, present evidence indicates that microinjections of an opiate into the PAG activate an efferent brainstem system that suppresses pain transmission at segmental (spinal cord) levels (See Figure 8.3). These observations indicate that analgesia elicited from the PAG requires a descending pathway to the spinal cord.

Pain Mechanisms

Ascending and Descending pain suppression mechanism

The primary ascending pain fibers (the A δ and C fibers) reach the dorsal horn of the spinal cord from peripheral sites to innervate the nociceptor neurons in Rexed laminae I & II. Cells from Rexed lamina II make synaptic connections in Rexed layers IV to VII. Cells, especially in laminae I and VII of the dorsal horn, give rise to ascending spinothalamic tracts. At the spinal level, opiate receptors are located at the presynaptic ends of the nocineurons and at the interneural level layers IV to VII in the dorsal horn. Activation of opiate receptors at the interneuronal level produces hyperpolarization of the neurons, which result in the inhibition of firing and the release of substance P, a neurotransmitter involved in pain transmission, thereby blocking pain transmission. The circuit that consists of the periaqueductal gray (PAG) matter in the upper brain stem, the locus coeruleus (LC), the nucleus raphe magnus (NRM) and the nucleus reticularis gigantocellularis (Rgc) contributes to the descending pain suppression pathway, which inhibits incoming pain information at the spinal cord level.

As mentioned previously, opioids interact with the opiate receptors at different CNS levels. These opiate receptors are the normal target sites for neurotransmitters and endogenous opiates such as the endorphins and enkephalins. As a result of binding at the receptor in subcortical sites, secondary changes which lead to a change in the electrophysiological properties of these neurons and modulation of the ascending pain information.

What activates the PAG to exert its effects? It was found that noxious stimulation excites neurons in the nucleus reticularis gigantocellularis (RGC). The nucleus Rgc innervates both the PAG and NRM. The PAG sends axons to NRM, and neurons in NRM send their axons to the spinal cord. Moreover, bilateral dorsolateral funiculus (DLF) lesions (DLFX) block the analgesia produced by both electrical stimulation and by microinjection of opiates directly into the PAG and NRM, but they only attenuate the systemic analgesic effects of opiates (Figure 8.4). These observations support the hypothesis that discrete descending pathways in the DLF are necessary for both OA and SPA.

The DLF is comprised of fibers originating from several brainstem nuclei, which are serotonergic (5-HT) from neurons located within the nucleus raphe magnus (NRM); dopaminergic neurons originating from ventral tegmental area (VTA) and adrenergic neurons originating from the locus coeruleus (LC). These descending fibers suppress noxious input at the nociceptive spinal cord neurons in laminae I, II, and V.

Opiate receptors have also been found in the dorsal horn of the spinal cord, mainly in Rexed laminae I, II, and V, and these spinal opiate receptors mediate inhibitory effects on dorsal horn neurons transmitting nociceptive information. The action of morphine appears to be exerted both in the spinal cord and brainstem nuclei (i.e., PAG and NRM). Systemic morphine acts on both brain stem and spinal cord opiate receptors to produce analgesia. Morphine binds the brainstem opiate receptors, which activates the brainstem descending serotonergic pathway to spinal cord (i.e., the DLF), and they have an opioid-mediated synapse at the level of the spinal cord.

This observation suggests that noxious stimuli (rather than non-noxious stimulus - see Gate Theory) are critical for activation of the descending pain modulation circuit (i.e., pain suppresses pain via the descending DLF pathway).

In addition, there are ascending connections from the PAG and raphe nuclei to PF-CM complex. These thalamic areas are part of the ascending pain modulation at the diencephalon level.

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