Itch and analgesia resulting from intrathecal application of morphine: contrasting effects on different populations of trigeminothalamic tract neurons

Abstract

Intrathecal application of morphine is among the most powerful methods used to treat severe chronic pain. However, this approach commonly produces itch sufficiently severe that patients are forced to choose between relief of pain or itch. The neuronal populations responsible for processing and transmitting information underlying itch caused by intrathecal application of morphine have not been identified and characterized. We describe two populations of antidromically identified trigeminothalamic tract (VTT) neurons in anesthetized rats that are differentially affected by morphine and explain several aspects of opioid-induced itch and analgesia. We found that intrathecal application of morphine increased ongoing activity of itch-responsive VTT neurons. In addition, intrathecal application of morphine increased responses to pruritogens injected into the skin and greatly heightened responses to innocuous mechanical stimuli. In contrast, the ongoing activity and responses to noxious pinches in nociceptive VTT neurons were frequently inhibited by the same dose of morphine. These results reveal that i.t. application of morphine affects specific subpopulations of VTT neurons in ways that may produce itch, hyperknesis, alloknesis, and analgesia.

Figure 1.

Example of activation of a pruriceptive VTT neuron by intrathecal (i.t.) application of morphine. A, Lesion at the recording point (arrow) in sDH of C1 segment. B, Receptive field. C, Ten overlaid spike traces exhibit ability to follow high-frequency stimulus train with a fixed latency (11.4 ms) between antidromic stimulation (25 μA) and recorded spike (top), and collision of orthodromic spike (arrow) with antidromic spike (asterisk at expected latency) (bottom). D, Lesion at the stimulation point (arrow) in the thalamus. 3V, third ventricle; Po, posterior nucleus; ml, medial lemniscus; ic, internal capsule. E, Responses to brush, pressure, and pinch. F, Response to intradermal (i.d.) injection of serotonin (5-HT) into the receptive field, i.t. application of vehicle and morphine, and intravenous injection of naloxone. Onset of i.d. and i.v. injections denoted by arrows; onset of i.t. application denoted by dotted line, with duration denoted by shading. Insets, Ten overlaid consecutive spike traces, beginning at arrow.

Figure 2.

Example of inhibition of a nociceptive (nonpruriceptive) VTT neuron by intrathecal (i.t.) application of morphine. A, Lesion at the recording point (arrow) in the sDH of caudal medulla. B, Receptive field. C, Lesion at the stimulation point (arrow) in thalamus. Hb, habenular nucleus; PF, parafascicular nucleus, others are as in Fig. 1. D, Responses to brush, pressure, and pinch. E, Firing levels following intradermal (i.d.) injections of vehicle, serotonin, histamine (HA), chloroquine (CQ), and BAM8–22 (BAM) into the receptive field. F, Responses during i.t. application of vehicle and morphine, and intravenous injection of naloxone.

Figure 3.

Mean responses of VTT neurons to intrathecal (i.t.) application of morphine. A, Mean histogram (3 s bins) of response of pruriceptive cells (n = 11) to i.t. application of vehicle and morphine, and intravenous injection of naloxone during an ongoing response to a pruritogen. Gray bars represent SEM. B, Mean changes in firing rate for pruriceptive cells during four conditions. Dotted line indicates level of no change. *, Statistically significant difference from vehicle. C, Discharge rates for each pruriceptive cell, including cells responsive to serotonin (black), histamine (gray), and chloroquine (white), during baseline and after i.t. application of morphine. Arrow indicates cell used in Figure 1. D, Mean histogram (3 s bins) of response of nociceptive cells (n = 11) to i.t. application of vehicle and morphine, and intravenous injection of naloxone during ongoing activity. E, Mean changes in firing rates for nociceptive cells during four conditions. *, Statistically significant difference from vehicle. Error bar for Morphine, intravenous condition too small to visualize (SEM = 0.0098). F, Discharge rates for each nociceptive cell during baseline and after i.t. application of morphine. Arrow indicates cell used in Figure 2.

Figure 4.

Effects of intrathecal (i.t.) application of morphine on responses to the pruritogen serotonin. A, Example of responses of a single cell to intradermal (i.d.) injections of vehicle and serotonin into the receptive field under baseline conditions, to a second i.d. injection of serotonin 15 min after i.t. application of vehicle, and to a third i.d. injection of serotonin 15 min after i.t. application of morphine. B, Effects of i.t. application of vehicle or morphine on mean response to subsequent application of serotonin (n = 4).

Figure 5.

Differing effects of intrathecal (i.t.) application of morphine on responses to innocuous brushing. A, Example of a pruriceptive VTT neuron's baseline response to brushing and greatly increased response in the presence of morphine. B, Mean histograms of response of pruriceptive cells (n = 10) to brushing under three conditions. C, Example of a nociceptive VTT neuron's baseline response to brushing and similar response in the presence of morphine. D, Mean histograms of response of nociceptive cells (n = 10) to brushing under three conditions. E, Normalized mean discharge rates during brushing for pruriceptive cells during four conditions. F, Effects of i.t. application of vehicle and morphine on normalized mean responses of nociceptive, pruriceptive, and low-threshold (n = 5) VTT neurons to brushing.

Figure 6.

Differing effects of intrathecal (i.t.) application of morphine on responses to noxious pinching. A, Example of a pruriceptive VTT neuron's baseline response to pinching and similar response in the presence of morphine. B, Mean histograms of responses of pruriceptive cells (n = 10) to pinching under three conditions. C, Example of a nociceptive VTT neuron's baseline response to pinching and greatly reduced response in the presence of morphine. D, Mean histogram of responses of nociceptive cells (n = 10) to pinching under three conditions. E, Normalized mean discharge rates during pinching for nociceptive cells during four conditions. F, Effects of i.t. application of vehicle and morphine on normalized mean responses of nociceptive and pruriceptive VTT neurons to pinching.

Figure 7.

Schematic diagram illustrating potential changes to inputs and outputs of VTT neurons caused by intrathecal (i.t.) application of morphine. A, Under normal conditions, nociceptive VTT neurons (red) receive painful and innocuous input while pruriceptive VTT neurons (green) receive painful, innocuous, and itchy input. B, During i.t. application of morphine, painful input is decreased to nociceptive VTT neurons and innocuous and itchy input is increased to pruriceptive neurons, resulting in reduced pain and increased itch sensations. Although inputs are denoted with a single arrow, these inputs could be either monosynaptic or polysynaptic. Changes in relative strength of inputs and outputs in presence of morphine are indicated by changes in thickness of lines.