Extracellular ATP is implicated in numerous sensory processes ranging from the response to pain to the regulation of motility in visceral organs. The ATP receptor P2X3 is selectively expressed on small diameter sensory neurons, supporting this hypothesis. Here we show that mice deficient in P2X3 lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X3 deficiency also causes a reduction in the sustained ATP-induced currents in nodose ganglion neurons. P2X3-null mice have reduced pain-related behaviour in response to injection of ATP and formalin. Significantly, P2X3-null mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased voiding frequency and increased bladder capacity, but normal bladder pressures. Immunohistochemical studies localize P2X3 to nerve fibres innervating the urinary bladder of wild-type mice, and show that loss of P2X3 does not alter sensory neuron innervation density. Thus, P2X3 is critical for peripheral pain responses and afferent pathways controlling urinary bladder volume reflexes. Antagonists to P2X3 may therefore have therapeutic potential in the treatment of disorders of urine storage and voiding such as overactive bladder.

1 The role of a 2 -adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the a 2 AR selective agonist dexmedetomidine (Dex) in mice devoid of individual a 2 AR subtypes through either a point (a 2A ) or null (a 2B /a 2C ) mutation (`knock-out').2 In a rodent model of acute thermal nociception, the mouse tail immersion test, Dex, in wild type (WT) control animals, produced a dose-dependent increase in the threshold for tail withdrawal from a 528C water bath with mean ED 50 values of 99.9+14.5 (a 2A ), 94.6+17.8 (a 2B ) and 116.0+17.1 (a 2C ) mg kg 71 , i.p. 3 In comparison to the WT controls, Dex (100 ± 1000 mg kg 71 , i.p.), was completely ine ective as an antinociceptive agent in the tail immersion test in the a 2A AR D79N mutant animals. Conversely, in the a 2B AR and a 2C AR knock-outs, Dex produced a dose-dependent antinociceptive e ect that was not signi®cantly di erent from that observed in WT controls, with ED 50 values of 85.9+15.0 (P40.05 vs WT control) and 226.0+62.7 (P40.05 vs WT control) mg kg 71 i.p., respectively. 4 Dex (10 ± 300 mg kg 71 , i.p.) produced a dose-dependent reduction in spontaneous locomotor activity in the a 2A , a 2B and a 2C AR WT control animals with ED 50 values of 30.1+9.0, 23.5+7.1 and 32.3+4.6 mg kg 71 , i.p., respectively. Again, Dex (100 ± 1000 mg kg 71 , i.p.) was ine ective at modulating motor behaviour in the a 2A AR D79N mutants. In the a 2B AR and a 2C AR knock-out mice, Dex produced a dose-dependent reduction in spontaneous locomotor activity with ED 50 values of 29.1+6.4 (P40.05 vs WT control) and 57.5+11.3 (P40.05 vs WT control) mg kg 71 , respectively. 5 Dex was also found to produce a dose-dependent reduction in body temperature in the a 2A , a 2B and a 2C AR WT control mice with ED 50 values of 60.6+11.0, 16.2+2.5 and 47.2+9.1 mg kg 71 , i.p., respectively. In the a 2A AR D79N mutants, Dex had no e ect on body temperature at a dose (100 mg kg 71 , i.p.) that produced a signi®cant reduction (76.2+0.58C; P50.01 vs vehicle) in temperature in WT controls. However, higher doses of Dex (300 and 1000 mg kg 71 , i.p) produced a small, but statistically signi®cant decrease in temperature corresponding to 71.7+0.48C and 72.4+0.38C (both P50.01 vs vehicle), respectively. In the a 2B AR and a 2C AR knock-out mice, Dex produced a dose-dependent reduction in body temperature with ED 50 values of 28.4+4.8 (P40.05 vs WT control) and 54.1+8.0 (P40.05 vs WT control) mg kg 71 , respectively. 6 In conclusion, the data are consistent with the a 2A AR being the predominant subtype involved in the mediation of the antinociceptive, sedative and hypothermic actions of Dex. This pro®le would appear to indicate that an a 2A AR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration.

No abstract

These results support a role for 5-HT2A receptor modulation in NREM sleep and suggest a previously unrecognized role for 5-HT6 receptors in sleep-wake regulation.

1 There is evidence that noradrenaline contributes to the development and maintenance of neuropathic pain produced by trauma to a peripheral nerve. It is, however, unclear which subtype(s) of a adrenergic receptors (AR) may be involved. In addition to pro-nociceptive actions of AR stimulation, a 2 AR agonists produce antinociceptive eects. 2 Here we studied the contribution of the a 2 AR subtypes, a 2A , a 2B and a 2C to the development of neuropathic pain. We also examined the antinociceptive eect produced by the a 2 AR agonist dexmedetomidine in nerve-injured mice. 3 The studies were performed in mice that carry either a point (a 2A ) or a null (a 2B and a 2C ) mutation in the gene encoding the a 2 AR. To induce a neuropathic pain condition, we partially ligated the sciatic nerve and measured changes in thermal and mechanical sensitivity. 4 Baseline mechanical and thermal withdrawal thresholds were similar in all mutant and wild-type mice; and, after peripheral nerve injury, all mice developed comparable hypersensitivity (allodynia) to thermal and mechanical stimulation. 5 Dexmedetomidine reversed the allodynia at a low dose (3 mg kg 71 , s.c.) and produced antinociceptive eects at higher doses (10 ± 30 mg kg 71) in all groups except in a 2A AR mutant mice. The eect of dexmedetomidine was reversed by intrathecal, but not systemic, injection of the a 2 AR antagonist RS 42206. 6 These results suggest that neither a 2A , a 2B nor a 2C AR is required for the development of neuropathic pain after peripheral nerve injury, however, the spinal a 2A AR is essential for the antinociceptive eects of dexmedetomidine.