OBJECTIVE-To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. METHODS-Inflammatory mediators (IM)were applied to the dura of unanesthetized rats via previously implanted cannulas and sensory thresholds of the face and hindpaws were characterized.RESULTS-IM elicited robust facial and hindpaw allodynia which peaked within 3 hr. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in treatment of migraine, including sumatriptan, naproxen, and a CGRP-antagonist. Consistent with clinical observations the allodynia was unaffected by an NK-1 antagonist. Having established facial and hindpaw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM ON cells and transient suppression of RVM OFF cells following IM.INTERPRETATION-Facial and hindpaw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia and are consistent with a brainstem generator of allodynia associated with headache disorders.

Activation of histamine H 3 receptors (H 3 Rs) reduces inflammation and nociception, but the existence of H 3 Rs on peripheral innervation has never been demonstrated. Here we use antibodies to locate H 3 Rs in whisker pads, hairy and glabrous hind paw skin, dorsal root ganglia (DRGs), and spinal cords of rats, wild-type mice, and H 3 R knockout (H 3 KO) mice. Although H 3 Rs have been hypothesized to be on C and sympathetic fibers, H 3 R-like immunoreactivity (H 3 R-LI) was only detected on presumptive periarterial Aδ fibers and on Aβ fibers that terminated in Meissner's corpuscles and as lanceolate endings around hair follicles. The H 3 R-positive periarterial fibers were thin-caliber and coexpressed immunoreactivity for calcitonin gene-related peptide (CGRP), substance P, acid sensing ion channel 3 and 200kD neurofilament protein (NF). H 3 R-LI was also detected on epidermal keratinocytes and Merkel cells, but not on Merkel endings, C fibers, any other Aδ fibers, or sympathetic fibers. In DRGs, H 3 R-LI was preponderantly on medium to large neurons coexpressing NF-LI and mostly CGRP-LI. In dorsal horn, CGRP-positive fibers with and without H 3 R-LI ramified extensively in lamina II; many of the former formed a plexus in lamina V. Low levels of H 3 R-LI were also present on Aβ fibers penetrating superficial and into deeper laminae. The distribution of H 3 R-LI was similar in rats and wild-type mice, but was eliminated or strongly reduced in Aδ fibers and Aβ fibers, respectively, in H 3 KO mice. Taken with recently published behavioral results, the present findings suggest that periarterial, peptidergic, H 3 R-containing Aδ fibers may be sources of high threshold mechanical nociception.

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Pharmacological activation of histamine H3 receptors is known to reduce the release of inflammatory peptides, thereby reducing pain and inflammation, but the site(s) and mechanism(s) of these effects are currently unknown. The present study addressed these questions by examining the effects of the H3 agonist immepip and the H3 antagonist thioperamide on nociceptive behaviors and swelling produced during the rat formalin test. Systemic administration of immepip (5 and 30 mg/kg, s.c.) significantly attenuated formalin-induced flinching but not licking responses during both phases. This attenuation was reversed by either systemic (15 mg/kg, i.p.) or intrathecal (20 or 50 microg) administration of thioperamide. Furthermore, immepip (30 mg/kg, s.c.) significantly inhibited formalin-induced swelling, an action which was completely reversed by systemic (15 mg/kg, i.p.), but not intrathecal (50 microg) thioperamide. Also consistent with this pattern, intrathecal immepip (50 microg) reduced flinching responses, but had no effect on formalin-induced paw swelling. The present findings suggest that activation of H3 receptors located on peripheral and spinal terminals of deep dermal fibers attenuates formalin-induced swelling and flinching, respectively. Pharmacological stimulation of H3 receptors could be an important therapeutic approach for many disorders related to deep dermal or inflammatory pain.