Analgesia by intrathecal delta-9-tetrahydrocannabinol is dependent on Cav3.2 calcium channels.

Delta-9-tetrahydrocannabinol (Δ9-THC) is known to produce systemic analgesia that involves CB1 and CB2 cannabinoid receptors. However, there is compelling evidence that Δ9-THC can potently inhibit Cav3.2T-type calcium channels which are highly expressed in dorsal root ganglion neurons and in the dorsal horn of the spinal cord. Here, we investigated whether spinal analgesia produced by Δ9-THC involves Cav3.2 channels vis a vis cannabinoid receptors. We show that spinally delivered Δ9-THC produced dose-dependent and long-lasting mechanical anti-hyperalgesia in neuropathic mice, and showed potent analgesic effects in models of inflammatory pain induced by formalin or Complete Freund's Adjuvant (CFA) injection into the hind paw, with the latter showing no overt sex differences. The Δ9-THC mediated reversal of thermal hyperalgesia in the CFA model was abolished in Cav3.2 null mice, but was unaltered in CB1 and CB2 null animals. Hence, the analgesic effects of spinally delivered Δ9-THC are due to an action on T-type calcium channels, rather than activation of spinal cannabinoid receptors.

TRPV1 Nociceptor Activity Initiates USP5/T-type Channel-Mediated Plasticity.

Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased pain sensitivity. Here, we have explored the role of afferent fiber activity in this process. Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors, but not that of non-nociceptive fibers, resulted in enhanced expression of USP5 in mouse dorsal root ganglia and spinal dorsal horn, along with decreased withdrawal thresholds for thermal and mechanical stimuli that abated after 24 hr. This sensitization was drastically reduced by an interfering peptide that prevented USP5-Cav3.2 association. Sensitization was relieved by pharmacological block of TRPV1 afferents, but not of myelinated neurons. In spinal cord slice recordings, we could optogenetically trigger an activity-dependent potentiation of presynaptic neurotransmission in the spinal dorsal horn that relied on Cav3.2 channel activity. This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the pain pathway.

Antinociceptive effect of crude extract, fractions and three alkaloids obtained from fruits of Piper tuberculatum.

This study investigated the possible antinociceptive effect of the crude extract, fractions and pure compounds (three alkaloids) obtained from fruits of Piper tuberculatum JACQ. (Piperaceae) in acetic acid-induced visceral pain in mice. Oral administration of crude extract and fractions (CH(2)Cl(2), EtOAc, methanol and hexane) (3-300 mg kg(-1)) caused a dose-related and significant inhibition of the acetic acid-induced visceral nociceptive response. The crude extract, dichloromethane (CH(2)Cl(2)) and ethyl acetate (EtOAc) fractions were more potent than methanol and hexane fractions. The isolated alkaloids dihydro-piplartine, piplartine and 3,4,5-trimethoxydihydrocinnamic acid (0.0001-30 mg kg(-1)) exhibited significant and dose-related antinociceptive effects against acetic acid-induced visceral pain. The results show, for the first time, that crude extract, fractions and pure compounds obtained from P. tuberculatum produce marked antinociception against the acetic acid-induced visceral nociceptive response, supporting the ethnomedical use of P. tuberculatum.

Involvement of cellular prion protein in the nociceptive response in mice.

The role of the cellular prion protein (PrP(c)) in neuronal functioning includes neuronal excitability, cellular adhesion, neurite outgrowth and maintenance. Here we investigated the putative involvement of the PrP(c) function on the nociceptive response using PrP(c) null (Prnp(0/0)) and wild-type (Prnp(+/+)) mice submitted to thermal and chemical models of nociception. PrP(c) null mice were more resistant than wild-type mice to thermal nociception of the tail-flick test. However, no significant difference was found on the hot plate test. In the acetic acid-induced visceral nociception, PrP(c) null mice showed an enhanced response when compared to wild-type mice. However, there was no difference between Prnp(0/0) and wild-type mice on glutamate- and formalin-induced licking behaviour and Freund's Complete Adjuvant (FCA)-induced mechanical allodynia. PrP(c) null mice developed significantly lower paw edema than wild-type mice. In addition, the visceral conditioning stimuli produced by a previous injection of acetic acid (20 days before testing) significantly reduced early and late phases of formalin-induced nociception in wild-type mice. In contrast, the same pre-treatment did not alter the formalin response in PrP(c) null mice. These results indicate a role of PrP(c) in the nociceptive transmission, including the thermal tail-flick test and visceral inflammatory nociception (acetic acid-induced abdominal constriction). Our findings show that PrP(c) is involved with a response mediated by inflammation (paw edema) and by visceral conditioning stimuli.