n(6)-cyclohexyladenosine and Inflammation

Water immersion is widely used in physiotherapy and might relieve pain, probably by activating several distinct somatosensory modalities, including tactile, pressure, and thermal sensations. However, the endogenous mechanisms behind this effect remain poorly understood. This study examined whether warm water immersion therapy (WWIT) produces an antiallodynic effect in a model of localized inflammation and whether peripheral opioid, cannabinoid, and adenosine receptors are involved in this effect. Mice were injected with complete Freund's adjuvant (CFA; intraplantar; i.pl.). The withdrawal frequency to mechanical stimuli (von Frey test) was used to determine 1) the effect of WWIT against CFA-induced allodynia and 2) the effect of i.pl. preadministration of naloxone (a nonselective opioid receptor antagonist; 5 µg/paw), caffeine (a nonselective adenosine receptor antagonist; 150 nmol/paw), 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; a selective adenosine A1 receptor antagonist; 10 nmol/paw), and AM630 (a selective cannabinoid receptor type 2 antagonist; 4 µg/paw) on the antiallodynic effect of WWIT against CFA-induced allodynia. Moreover, the influence of WWIT on paw inflammatory edema was measured with a digital micrometer. WWIT produced a significant time-dependent reduction of paw inflammatory allodynia but did not influence paw edema induced by CFA. Naloxone, caffeine, DPCPX, and AM630 injected in the right, but not in the left, hind paw significantly reversed the antiallodynic effect of WWIT. This is the first study to demonstrate the involvement of peripheral receptors in the antiallodynic effect of WWIT in a murine model of persistent inflammatory pain.

Topics: Adenosine; Animals; Benzoxazines; Disease Models, Animal; Edema; Freund's Adjuvant; Hyperalgesia; Immersion; Indoles; Inflammation; Male; Mice; Morpholines; Naloxone; Naphthalenes; Narcotic Antagonists; Neurobiology; Pain Measurement; Receptor, Adenosine A1; Receptor, Cannabinoid, CB2; Receptors, Opioid; Water Purification

Antinociception induced by the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is linked to opioid receptors. We studied the subtype of receptors to which CPA action is related, as well as a possible enhancement of antinociception when CPA is coadministered with opioid receptor agonists. Spinal cord neuronal nociceptive responses of male Wistar rats with inflammation were recorded using the single motor unit technique. CPA antinociception was challenged with naloxone or norbinaltorphimine. The antinociceptive activity of fentanyl and U-50488H was studied alone and combined with CPA. Reversal of CPA antinociception was observed with norbinaltorphimine (82.9±13% of control) but not with low doses of naloxone (27±8% of control), indicating an involvement of κ-opioid but not µ-opioid receptors. Low doses of CPA did not modify fentanyl antinociception. However, a significant enhancement of the duration of antinociception was seen when U-50488H was coadministered with CPA. We conclude that antinociception mediated by CPA in the spinal cord is associated with activation of κ-opioid but not µ-opioid receptors in inflammation. In addition, coadministration of CPA and κ-opioid receptor agonists is followed by significantly longer antinociception, opening new perspectives in the treatment of chronic inflammatory pain.

Topics: Adenosine; Animals; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Fentanyl; Inflammation; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid, kappa; Reflex; Spinal Cord

Spinal administration of adenosine inhibits neutrophil accumulation in skin. The neural pathways mediating this action are unknown. We investigated individually the roles of capsaicin sensitive primary afferent fibers, sympathetic efferent fibers, and dorsal roots in this regulation. One week after implantation of intrathecal (IT) catheters into rats, the adenosine receptor agonist cyclohexyladenosine (CHA) or vehicle was injected intrathecally. Inflammatory skin lesions were induced by intradermal carrageenan. Three hours later, skin was harvested and assayed for neutrophils by measuring myeloperoxidase (MPO) activity. Intrathecal CHA (5 microg/kg) decreased neutrophil infiltration into skin lesions. Nociceptive peptides were largely depleted from central terminals of primary afferents by IT capsaicin pretreatment. This depletion had no effect on either basal neutrophil infiltration or CHA-mediated modulation. Sympathetic fibers were largely destroyed by systemic 6-hydoxydopamine (6-OHDA) pretreatment; sympathectomy did not affect basal neutrophil infiltration or block its suppression by IT CHA. Thus, spinal adenosine effects on skin neutrophil trafficking appear to be independent of sympathetic nerves and primary afferent peptides, although incomplete lesions by chemical pretreatments may have confounded our results. Sensory fibers were interrupted by prior unilateral dorsal rhizotomies. This procedure had no effect on neutrophil accumulation in control rats. However, rhizotomy blocked the CHA effect, with MPO levels 45 +/- 18% greater in denervated than control skin in IT CHA-treated animals (P < 0.05). It is clear that the spinal adenosine effect requires intact somatic connectivity. Information on pain and inflammation in the periphery is transmitted to the nervous system, where increased spinal adenosine levels can suppress peripheral inflammation.

Topics: Adenosine; Animals; Capsaicin; Feedback; Inflammation; Injections, Spinal; Male; Nerve Fibers; Neurons, Afferent; Neuropeptides; Neutrophil Infiltration; Neutrophils; Oxidopamine; Rats; Rats, Sprague-Dawley; Skin; Spinal Cord; Spinal Nerve Roots; Sympathectomy, Chemical; Sympatholytics