Morphine (0.5, 5, and 45 nmol) administered in the lumbar spinal intrathecal space 20 minutes before intra-articular carrageenan decreased incapacitation (5 nmol, P = 0.000056, and 45 nmol, P = 0.0000064; Fig. 5A) and the articular diameter (45 nmol, P = 0.000702; Fig. 5B). Furthermore, combining a subanalgesic dose of morphine (0.5 nmol) with an equally subeffective dose either of the H3R agonist immepip (0.4 nmol) or of the H1R antagonist cetirizine (12.6 pmol) significantly decreased articular incapacitation although there was no significant effect on the articular diameter (morphine + immepip, P = 0.010291, and morphine + cetirizine, P =0.004411; Fig. 6, A and B). Similarly, combining a sub-antiedematogenic dose of morphine (5 nmol) with the same subeffective doses of immepip and cetirizine produced a potent inhibition of articular incapacitation (morphine + immepip, P = 0.000178, and morphine + cetirizine, P =0.003729; Fig. 6C) and also reduced articular diameter (morphine + immepip, P = 0.000029, and morphine + cetirizine, P =0.000049; Fig. 6D).
In the present study, it was found that a spinally administered H1R antagonist or H3R agonist can inhibit articular nociception and peripheral edema induced by intra-articular carrageenan and that both agents can also potentiate similar effects produced by morphine. The present results suggest that spinal histamine is involved not only in nociceptive processing but also in the control of peripheral inflammation.
Tuberomammillary nucleus of hypothalamus projects histaminergic axons to the spinal cord,5,6 but the role of histamine at this level is still poorly studied. Three types of histamine receptors—H1, H2, and H3—are found in the superficial lamina I and II of the dorsal horn.27–29 These laminae receive nociceptive information from C and Aδ polymodal primary sensory fibers.30 The antinociceptive and pronociceptive effects of H1R and H3R antagonists suggest that histamine is continuously released in the spinal cord during articular inflammation and has an active role in the processing of nociceptive information with opposing effects mediated by these 2 receptor types.
Several lines of evidence support a role for histamine H1R in pain processing at the spinal level. H1R activation has been shown to play a pronociceptive role in the dorsal horn.1,3,7 Thus, intrathecal injection of H1R antagonist elicits analgesia,31 whereas spinally injected morphine produces a greater antinociceptive effect in H1R knockout mice,32 and it has been suggested that the activation of histamine H1R in the spinal cord can increase sensitivity to a painful stimulus. However, H3R activation in the spinal cord has been found to exert an antinociceptive effect.33 The present findings corroborate current knowledge about the role of this signaling pathway in nociception. However, the observed effects of these drugs on peripheral inflammation add a new perspective for the control of arthritic conditions. The spinal cord is known to be a center that controls peripheral inflammation by altering antidromic activity in primary afferent nociceptors.21 Histamine, by modulating nociceptive sensitivity in the spinal cord, could therefore play a role in such control of peripheral inflammation. This assumption is in line with our finding that spinal injection both the H1R antagonist, cetirizine, and the H3R agonist, immepip, reduced articular edema.
DRRs are action potentials generated in the central branches of nociceptors, mainly running antidromically to the peripheral terminal.21 This phenomenon enhances inflammation by the release of vasoactive peptides, for example, substance P and Calcitonin Gene-Related Peptide (CGRP)34 and probably prostaglandin E2.35,36 Our working hypothesis is that histamine can potentiate both nociception and the generation of DRR, which would explain the enhancement of incapacitation and articular edema, respectively, by acting on H1Rs. However, the action of H3R seems to be responsible for the antinociceptive and antiedematogenic effects.
Although H1R is positively coupled to the adenilate cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway,37 the H3R has the opposite effect and inhibits via Gi protein. H3R activation has been shown to inhibit adenylate cyclase activity, thus reducing cAMP and Ca2+ levels.38–40 Primary afferent nociceptor sensitization is a phenomenon directly linked to the AC/cAMP/PKA pathway activation in rats41,42 and also involves PKCε.41,43,44 Thus, the molecular signaling of both histamine receptors fits well with the idea that primary afferent sensitization by H1R activation is responsible for the increase in either nociception or peripheral edema, whereas its desensitization by H3R activation causes the opposite effect.
Several studies have suggested that histamine receptors are involved in some pharmacological actions of morphine.12,13,32 In additional previous reports, we have shown that spinal administration of morphine produced a potent inhibitory effect on the carrageenan-induced paw edema.13,16 The present data suggest that spinal injection of opioids can also produce potent antinociception and antiedematogenic effects in the carrageenan-induced arthritis model. Furthermore, both the H1R antagonist, cetirizine, and the H3R agonist, immepip, produced a positive interaction with morphine in terms of either antinociceptive or antiedematogenic effects.
These kinds of interactions between opioids and histamine for nociceptive modulation have been shown in additional previous reports. For example, H1R antagonists administered subcutaneously potentiated opiate analgesia,45,46 whereas antinociception induced by morphine was significantly augmented in H1R knockout mice.32 In addition, it has been reported that H3R antagonists attenuate the antinociceptive effect produced by morphine47 and β-endorphin,12 whereas the H3R agonist, R-α-methylhistamine, potentiates the morphine analgesic effect in mice.47
Systemically delivered morphine was shown to facilitate histamine release in the periaqueductal gray,15 and intracerebroventricular injection of morphine, or other opioids, increased the turnover of brain histamine, suggesting that morphine acts on brain opioid receptors to stimulate the activity of histaminergic neurons.48 Clinical studies have also demonstrated that spinal cord administration of morphine results in the release of histamine.49 Because histamine has consistently been shown to be pronociceptive in the spinal cord and at other brain levels, it is conceivable that morphine-induced analgesia is antagonized by histamine release. Taking these data into account, it would be expected that the coadministration of morphine with either an H1R antagonist or an H3R agonist would result in a potentiation of the analgesic effect, as observed here. Furthermore, such reasoning also predicts a similar interaction upon the antiedematogenic effect produced by spinal morphine administration, which was indeed shown in the present study. The observed opioid-induced antiedematogenic effect highlights the importance of this central mechanism of inflammatory control and the convergence of such mechanism with that of nociception.
In conclusion, the present study brings additional support for the existence of central nervous system control of peripheral inflammation, also suggesting a role for spinal histaminergic receptors. The blockade of H1R and activation of H3 autoreceptors might be explored therapeutically to enhance the efficacy of intrathecal morphine.
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