Neuropathic pain is a common and often incapacitating clinical problem for which little useful therapy is presently available. Painful peripheral neuropathies can have many etiologies, among which are trauma, viral infections, exposure to radiation or chemotherapy, and metabolic or autoimmune diseases. Sufferers generally experience both pain at rest and exaggerated, painful sensitivity to light touch. Spontaneous firing of injured nerves is believed to play a critical role in the induction and maintenance of neuropathic pain syndromes. Using a well characterized nerve ligation model in the rat, we demonstrate that hyperpolarization-activated, cyclic nucleotide-modulated (HCN) "pacemaker" channels play a previously unrecognized role in both touch-related pain and spontaneous neuronal discharge originating in the damaged dorsal root ganglion. HCN channels, particularly HCN1, are abundantly expressed in rat primary afferent somata. Nerve injury markedly increases pacemaker currents in large-diameter dorsal root ganglion neurons and results in pacemaker-driven spontaneous action potentials in the ligated nerve. Pharmacological blockade of HCN activity using the specific inhibitor ZD7288 reverses abnormal hypersensitivity to light touch and decreases the firing frequency of ectopic discharges originating in Abeta and Adelta fibers by 90 and 40%, respectively, without conduction blockade. These findings suggest novel insights into the molecular basis of pain and the possibility of new, specific, effective pharmacological therapies.

Brain histamine H 3 receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H 3 receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H 3 receptors. This paper provides the first description of the H 3 receptor-deficient mouse (H 3 Ϫ/Ϫ ), including molecular and pharmacologic verification of the receptor deletion as well as phenotypic screens. The H 3 Ϫ/Ϫ mice showed a decrease in overall locomotion, wheel-running behavior, and body temperature during the dark phase but maintained normal circadian rhythmicity. H 3 Ϫ/Ϫ mice were insensitive to the wake-promoting effects of the H 3 receptor antagonist thioperamide. We also observed a slightly decreased stereotypic response to the dopamine releaser, methamphetamine, and an insensitivity to the amnesic effects of the cholinergic receptor antagonist, scopolamine. These data indicate that the H 3 receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine.The neurotransmitter histamine, which originates from tuberomamillary nuclei in the posterior hypothalamus, projects diffusely throughout the central nervous system (CNS) and has been implicated in the regulation of many functions, including sleep/wake, food and water intake, thermoregulation, memory, and other homeostatic processes (Wada et al., 1991;Brown et al., 2001). Four subtypes (H 1 , H 2 , H 3 , and H 4 ) of histamine receptors are currently recognized (Hill et al., 1997;Hough, 2001). The H 3 subtype is predominantly located presynaptically and serves as an autoreceptor to regulate the synthesis and release of histamine (Hill et al., 1997). The H 3 subtype also has heteroreceptor functions and influences CNS dopamine, ␥-aminobutyric acid, noradrenaline, acetylcholine, and serotonin levels (Arrang et al., 1983(Arrang et al., , 1987bSchlicker et al., 1988;Clapham and Kilpatrick, 1992;Hill et al., 1997). Behavioral correlates of H 3 receptor function have primarily been studied in the context of pharmacologically blocking the receptor using the specific H 3 receptor antagonist, thioperamide. For instance, thioperamide has been used to increase the amount of wakefulness (Monti et al., 1991), to prevent scopolamine-induced amnesia (Giovannini et al., 1999), and to decrease food intake (Itoh et al., 1999;Attoub et al., 2001) in rats. The recent cloning of the H 3 receptor in our laboratory (Lovenberg et al., 1999) has made it possible to create a transgenic line of mice devoid of H 3 receptors and to explore at a molecular level the importance of this receptor in a variety of behaviors. This paper provides the first description of 1) generating the H 3 receptor knockout mice, 2) verifying the d...

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